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Hepatocyte nuclear factor 1-related renal disease: an expanding clinical spectrum
Rhian L Clissold, Alexander J Hamilton, Andrew T Hattersley, Sian Ellard, Coralie Bingham
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Abstract
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Heterozygous mutations in the gene encoding the transcription factor hepatocyte nuclear factor 1
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(HNF1B), previously known as transcription factor 2 (TCF2), are the commonest known monogenic
7
cause of developmental kidney disease. Renal cysts are the most frequent feature but single kidneys,
8
hypoplasia, horseshoe kidneys, duplex kidneys, collecting system abnormalities, bilateral
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hydronephrosis and hyperuricaemic nephropathy are also seen. The disorder is often detected on
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prenatal ultrasound scanning, where bilateral hyperechogenic kidneys are usually found. HNF1B-
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related disease is a multi-system disorder. Many patients have young-onset diabetes, leading to the
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initial description of the renal cysts and diabetes (RCAD) syndrome. Other clinical features include
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pancreatic hypoplasia, genital tract malformations, abnormal liver function tests, hypomagnesaemia,
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hyperuricaemia and early-onset gout. Neurological features, including autism spectrum disorders,
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may be seen in patients with a whole-gene deletion. Half of cases have a heterozygous coding
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region/splice site mutation and half have a whole-gene deletion; both frequently arise
17
spontaneously so there is often no family history. The principal mechanism is haploinsufficiency with
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no clear genotype-phenotype correlation. Animal models looking at the expression of HNF1B suggest
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it plays an important role during several stages of nephrogenesis but the precise signalling pathways
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still need to be elucidated.
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Introduction
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Heterozygous mutations in the gene encoding the transcription factor hepatocyte nuclear factor 1
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(HNF1B) are the most common known monogenic cause of developmental renal disease.1-4 Renal
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cysts are the most consistent clinical feature and many affected individuals also have early-onset
27
diabetes, hence the naming of the HNF1B-associated disorder as the Renal Cysts and Diabetes
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(RCAD) syndrome.5 Since the initial description of the early cases, it has become clear that several
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other clinical features are also associated with mutations in this gene, and these include pancreatic
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hypoplasia,6, 7 genital tract malformations,8 deranged liver function tests,9, 10 hypomagnesaemia,11
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hyperuricaemia and early-onset gout.12 HNF1B-related disease is now considered a multi-system
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disorder (Figure 1).
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The discovery of HNF1B gene mutations as a cause of renal developmental disease came from
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unexpected findings in the study of maturity-onset diabetes of the young (MODY). MODY is a
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monogenic form of early-onset (typically diagnosed before 25 years) diabetes that is inherited in an
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autosomal dominant manner and results from pancreatic beta-cell dysfunction.13 The commonest
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cause of MODY is mutation of the gene encoding the transcription factor HNF1A,14 which binds to
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the same DNA sequence as HNF1B and both proteins show >80% sequence homology.15 This made
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HNF1B an excellent candidate gene for MODY and a mutation associated with young-onset diabetes
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in a Japanese family was first reported in 1997.16 Renal disease was also present in the three
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affected individuals, ranging from persistent proteinuria to chronic renal failure. Bilateral renal cysts
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were subsequently identified in the individual with proteinuria.9 This association of diabetes with
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non-diabetic renal disease was strengthened by the finding of two additional families with a
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heterozygous mutation in the HNF1B gene.8, 17 Several of these subjects were also found to have
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abnormal liver function tests and genital malformations, the first clues that this was a multi-system
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disease.
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In this Review, we focus on HNF1B-related renal developmental disease, with a description of the
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variable renal phenotype seen as well as the many extra-renal features that have been reported. We
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also summarise the molecular genetics of this disorder and discuss what has been learned from
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animal models about HNF1B expression during embryonic development. Finally, we highlight key
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areas for future research.
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Renal phenotype
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Prevalence
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Congenital abnormalities of the kidney and urinary tract (CAKUT) are a common cause of renal
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failure in the paediatric population.18 Several studies have confirmed that heterozygous mutations in
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the HNF1B gene are the most frequently identified genetic abnormality associated with
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developmental renal disease.1-3 Table 1 summarises the prevalence of HNF1B-related renal disease
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in different study cohorts of ≥50 subjects where both mutation and deletion screening of the HNF1B
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gene has been performed. The average overall detection rate is 19% but this varies from 5-31% and
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depends on the phenotypic selection of the cohort. In contrast, HNF1B gene anomalies are an
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infrequent cause of MODY and are likely to account for <1% of cases.19
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Table 1 ǀ Detection rate of HNF1B genetic abnormalities in study cohorts of ≥50 subjects with renal disease where both
mutation and deletion screening of the HNF1B gene has been performed
Study
Cohort
Detection rate
Reference
Ulinski et al., 2006
80 children with either renal cysts, hyperechogenicity,
25/80 (31%)
20
8/99 (8%)
3
18/62 (29%)
21
38/160 (24%)
22, 23
21/91 (23%)
11
5/50 (10%)
24
75/377 (20%)
4
4/73 (5%)
2
12/103 (12%)
1
hypoplasia or single kidney
Weber et al., 2006
99 unrelated European children with renal hypodysplasia and
chronic renal insufficiency (eGFR 15-75 ml/min/1.73 m2)
Decramer et al., 2007
62 foetuses with either cortical microcysts or isolated
hyperechogenicity/bilateral fetal hyperechogenic kidneys
Edghill et al., 2008
160 unrelated Caucasian subjects with unexplained renal
disease categorised as follows: renal cysts and cystic
dysplasia, glomerulocystic kidney disease, atypical familial
juvenile hyperuricaemic nephropathy, renal dysplasia, renal
malformations and other
Adalat et al., 2009
91 children with either renal cysts and diabetes, undiagnosed
renal cystic disease or index patients with kidney
malformations and a family history of renal disease, diabetes
or gout
Nakayama et al., 2010
50 Japanese subjects with either renal hypodysplasia,
unilateral multicystic dysplastic kidney, single kidney or cystic
kidneys
Heidet et al., 2010
377 unrelated subjects with either hyperechogenic kidneys
with size not more than +3 SD, multicystic kidney disease,
renal agenesis, renal hypoplasia, cystic dysplasia or
hyperuricaemic tubulointerstitial nephropathy not associated
with UMOD mutation
Thomas et al., 2011
73 North American children with renal aplasia or hypoplasia
enrolled in the Chronic Kidney Disease in Children study
(Schwartz-estimated GFR 30-90 ml/min/1.73 m2)
Madariaga et al., 2013
103 foetuses with very severe CAKUT that appeared isolated
by fetal ultrasound examination and led to termination of
pregnancy
Abbreviations: CAKUT, congenital abnormalities of the kidney and urinary tract; eGFR, estimated glomerular filtration rate;
SD, standard deviation.
4
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Morphology
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Considerable variation is seen in the phenotype of HNF1B-related renal abnormalities despite the
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single genetic aetiology. Morphological renal abnormalities are generally identified by ultrasound
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(US). Computerised tomography and magnetic resonance imaging (MRI) may be used in selected
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cases and can be useful in the detection of extra-renal features, such as pancreatic structural
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abnormalities. Affected children are often identified on prenatal US scanning, where the most
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frequent phenotype seen before birth is isolated bilateral hyperechogenic kidneys with normal or
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slightly increased size.21 In later life most of these individuals have normal-sized or small kidneys
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with hyperechogenicity and/or cortical cysts on imaging, which suggests a slowing down of renal
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growth after birth.4
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Cystic disease, including cystic dysplasia, is the main feature of HNF1B-related renal disease in both
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children and adults and was present in 73% of cases with HNF1B gene anomalies and various kidney
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phenotypes in the largest series described to date.4 It should be noted that the major caveat with
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determining the prevalence of different renal characteristics is that no population-based data exists
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and most of the existing cohorts described were pre-selected for particular kidney abnormalities.
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Cysts are usually small,20 arise within the renal cortex and there does not appear to be a progressive
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increase in the number of cysts over time.25 Single kidneys have been reported in 5/24 adult HNF1B
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mutation carriers, the largest series so far of adults with HNF1B disease.25 Single kidneys were
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initially hypothesised to be the result of involution of multicystic dysplastic kidneys over time but
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unilateral renal agenesis has also been seen on prenatal imaging of 4/56 affected children.4, 20
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Other structural abnormalities include renal hypoplasia, horseshoe kidney and duplex kidney.3, 20, 22
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Collecting system abnormalities, such as pelviureteric junction obstruction, are also seen, but these
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usually occur in conjunction with another form of renal structural abnormality.26 Bilateral
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hydronephrosis has been reported.11, 27 HNF1B gene anomalies have been found in 2/34 individuals
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with prune-belly syndrome, which is characterised by a triad of dilatation of the urinary tract,
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deficiency or absence of the abdominal wall musculature and bilateral undescended testes.27-29 In a
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minority of cases, renal imaging has been normal; however, it is unclear how often this occurs as
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most of the cohorts with HNF1B-related disease that have been studied were pre-selected for kidney
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abnormalities.6, 19, 25
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Histology
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Renal biopsies are not performed in many cases of HNF1B-related disease as renal cysts or other
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structural anomalies are often seen on imaging. Of the 19 histology results reported in the literature,
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the indication for biopsy is often unclear. Many were performed as part of the investigation of
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unexplained renal impairment prior to a genetic diagnosis being established and some have resulted
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from post-mortem examination following termination of pregnancy. There is considerable variation
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in the histological diagnosis. This includes hypoplastic glomerulocystic kidney disease (cortical
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glomerular cysts with dilatation of the Bowman spaces and primitive glomerular tufts in ≥5% of the
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cysts) in six cases,3-5, 30 oligomeganephronia (reduced number of enlarged nephrons) in three cases,6,
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8, 31
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arise from abnormal nephron development. Other non-specific features include interstitial fibrosis,
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enlarged glomeruli and nephrons plus glomerular cysts.6, 31
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Malignancy
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Imaging to screen for chromophobe renal cell carcinoma (RCC) should be considered in individuals
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with HNF1B gene anomalies. Following the observation of a chromophobe RCC in a patient with a
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known HNF1B mutation,6 a series of 34 randomly selected renal neoplasms were screened for
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HNF1B inactivation. Biallelic inactivation was identified in 1/11 chromophobe carcinoma samples
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due to the development of a somatic HNF1B gene deletion in addition to a germline mutation.34
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and cystic renal dysplasia in two cases.32, 33 All of these different renal phenotypes are likely to
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HNF1B overexpression is common in clear cell ovarian cancer.35 Several genome-wide association
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studies have also linked genetic variation in the HNF1B region with a risk of endometrial and
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prostate cancer.36-39
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Electrolyte abnormalities
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Hypomagnesaemia
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Hypomagnesaemia is a common feature of HNF1B-related disease.4,
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detected in 8/18 (44%) children under follow-up for renal malformation and found to have an HNF1B
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mutation; this was accompanied by hypermagnesuria and hypocalciuria. Apart from one individual
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who presented with tetany, symptoms attributable to the hypomagnesaemia were not reported in
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the other cases. HNF1B has been found to regulate the transcription of FXYD2, a gene that encodes
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the γ subunit of the Na+/K+-ATPase and is involved in the reabsorption of magnesium in the distal
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convoluted tubule.11, 40 Mutation of FXYD2 has been reported in one family to date with autosomal
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dominant hypomagnesaemia and hypocalciuria.41 This suggests an additional role for HNF1B in the
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maintenance of tubular function.
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Hyperuricaemia
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Hyperuricaemia is associated with HNF1B-related disease although serum urate levels have not been
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systematically measured in a large group of patients.12 Early-onset gout may also be seen; some
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affected individuals with hyperuricaemia, young-onset gout and renal disease have fitted established
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criteria for familial juvenile hyperuricaemic nephropathy, a condition usually caused by mutations in
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the UMOD gene encoding uromodulin.42 The cause of hyperuricaemia in HNF1B-related disease is
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likely both a reflection of altered urate transport in the kidney and an early manifestation of renal
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impairment. Mice with renal-specific inactivation of HNF1B have markedly reduced transcriptional
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activation of Umod.43 UMOD mutations that result in familial hyperuricaemic nephropathy are
7
11, 25
Hypomagnesaemia was
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thought to exert a dominant negative effect so it currently remains unclear as to how the same
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phenotype is associated with HNF1B haploinsufficiency.4
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Renal function
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Renal function in HNF1B-related disease is usually impaired but can range from normal to end-stage
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renal disease (ESRD). A slowly progressive deterioration in renal function throughout adulthood has
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been described; a median yearly estimated glomerular filtration rate (eGFR) decline of -2.45 ml/min
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per 1.73 m2 was seen in a study of 27 adults with an HNF1B mutation and a wide variety of renal
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phenotypes.25 Four patients (15%) in this series progressed to ESRD, which is very similar to the
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frequency of 12.8% reported in a recent systematic review.26 However, the age at diagnosis of ESRD
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remains unpredictable. The impact of HNF1B gene anomalies on renal function in the paediatric
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population is harder to interpret due to the young age of the children and lack of long-term follow-
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up. ESRD has been reported in early childhood.22 HNF1B mutations can also be associated with
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severe prenatal renal anomalies, which may result in anamnios, pulmonary hypoplasia and renal
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failure. This in turn can lead to parental request for termination of pregnancy, perinatal death or the
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need for very early renal replacement therapy.1, 4
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Renal transplantation should be considered for individuals with HNF1B-related disease who are
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approaching ESRD. As they are at risk of developing early new-onset diabetes after transplantation
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(NODAT), an immunosuppressive regimen that avoids tacrolimus and reduces corticosteroid
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exposure may be beneficial.44 Simultaneous pancreas and kidney transplantation (SPK) may be an
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option for those HNF1B patients with both diabetes and ESRD, a procedure usually reserved for
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patients with type 1 diabetes and ESRD. Three individuals with HNF1B-related disease have been
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successfully treated with either SPK or pancreas after kidney transplantation and remained insulin-
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free one year post-procedure.45, 46
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Differential diagnosis
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The differential diagnosis of HNF1B-related kidney disease is wide given the considerable variation
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seen in the renal phenotype so only the most common presentations are discussed here. As it is
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often identified on prenatal US scanning for those patients that present in childhood, the differential
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diagnosis is usually that of moderately enlarged bilateral hyperechogenic kidneys. Autosomal
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recessive and autosomal dominant polycystic kidney diseases are the main considerations in this
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case.47 To aid diagnosis, imaging also needs to assess for any associated extra-renal abnormalities
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and a family history will be useful with particular emphasis on renal disease and diabetes. Renal
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cysts are visualised more often after birth; Table 2 summarises the main differential diagnoses to
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consider depending on the age of presentation. Individuals with HNF1B-related kidney disease may
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have another form of renal tract malformation, such as renal agenesis or hypoplasia. The differential
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diagnosis in these cases can include other multiorgan syndromes but these are not covered in this
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Review.
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Table 2 ǀ Differential diagnosis of renal cysts depending on common age of presentation.47-49
Age
Differential diagnosis
Key distinguishing features
Diagnostic tests
Childhood
Early-onset ADPKD
FH; diffuse cortical cysts
Renal US; PKD1 and PKD2
genetic testing in selected cases
ARPKD
Medullary cysts; oligohydramnios with
Renal and abdominal US; PKHD1
Potter’s phenotype, absent urine from
genetic testing in selected cases
the fetal bladder and pulmonary
hypoplasia in severe cases; congenital
hepatic fibrosis
Cystic dysplasia
Echobright kidneys with cysts and
Renal US and 99mTc-DMSA
(idiopathic)
decreased corticomedullary
renography
differentiation; absence of extra-renal
features
Multicystic dysplastic
Unilateral; multiple unconnected cysts of
Renal US and 99mTc-DMSA
kidney (idiopathic)
varying size; absent renal pelvis and renal renography
parenchyma; absence of extra-renal
features
Nephronophthisis
Small kidneys with corticomedullary
NPHP genetic testing; renal
junction cysts; associated with several
biopsy in selected cases
extra-renal features including retinitis
pigmentosa and ocular motor apraxia
Obstructive dysplasia
Dilated upper tract
Renal US
Tuberous sclerosis
Cysts and angiomyolipomas; skin
Dermatological and ophthalmic
fibromas; CNS involvement
evaluation; cranial MRI; renal
US; TSC1 and TSC2 genetic
testing in selected cases
Adulthood
Acquired cysts
Long duration of renal
Renal US
impairment/dialysis; shrunken kidneys;
no FH
ADPKD
Extra-renal cysts in liver, pancreas and
Renal and abdominal US; cranial
spleen; intracerebral aneurysms; cardiac
MRA in selected cases; PKD1
valvular abnormalities
and PKD2 genetic testing in
Ravine criteria:
selected cases
<30, +FH 2 cysts either kidney, -FH 5 cysts
either kidney
30-60 years, +FH 4 cysts either kidney, FH 5 cysts either kidney
>60 years, +FH 8 cysts either kidney, -FH 8
cysts either kidney
ARPKD
Medullary cysts; hepatic periportal
Renal and abdominal US; PKHD1
fibrosis; portal hypertension
genetic testing in selected cases
Medullary sponge kidney
Normal-sized kidneys or renal
No diagnostic tests
hypertrophy with echogenic medullary
recommended as benign
pyramids and calcification; usually
condition with no specific
asymptomatic but may be associated with treatment
urinary tract infection and nephrolithiasis
Simple cysts
Cortical cysts; normal-sized kidneys;
Renal US
absence of extra-renal features
Von Hippel-Lindau
Multiple tumours in the CNS, retina,
Renal US +/- CT/MRI; 24 hour
adrenal gland, pancreas and kidney; renal urine collection for
cell carcinomas
catecholamines and
metanephrines; VHL genetic
testing
Abbreviations: ADPKD, autosomal dominant polycystic kidney disease; ARPKD, autosomal recessive polycystic kidney
disease; CT, computerised tomography; HNF1B, hepatocyte nuclear factor 1; FH, family history; MRA, magnetic resonance
angiography; MRI, magnetic resonance imaging; 99mTc-DMSA renography, technetium-99m-labelled dimercaptosuccinic
acid; US, ultrasound.
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Extra-renal phenotype
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Diabetes mellitus
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HNF1B plays an important role in the early development and differentiation of the pancreas.50, 51
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HNF1B gene anomalies therefore result in both reduced endocrine and exocrine function. Diabetes
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is the most common extra-renal phenotype seen and usually presents after the renal disease for
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those patients with an HNF1B-related disorder identified in childhood. The mean age at diagnosis of
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diabetes is 24 years26 but this can vary from the neonatal period52, 53 to late middle age.23 It may
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manifest as NODAT and HNF1B gene analysis should be considered in individuals with unexplained
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CAKUT undergoing transplantation in order to improve post-transplant management.44 Presentation
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with diabetic ketoacidosis has also been described.54 The majority of patients respond poorly to
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sulphonylurea therapy, unlike individuals with an HNF1A gene mutation who are extremely
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sensitive, and require treatment with insulin.26, 55
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The pathophysiology is due to a combination of -cell dysfunction and insulin resistance. -cell
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dysfunction results in reduced insulin secretion and this is likely to be a consequence of pancreatic
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hypoplasia.7 Decreased insulin secretion in utero leads to intrauterine growth retardation and low
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birth weight.53 Patients with HNF1B mutations have reduced insulin sensitivity of endogenous
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glucose production but peripheral insulin sensitivity is normal.56 This results in hyperinsulinaemia
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and associated dyslipidaemia, with raised triglycerides and reduced high-density lipoprotein.55
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Exocrine pancreatic dysfunction
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Pancreatic hypoplasia has been described in several individuals with HNF1B-related disease.6 In
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particular, imaging has shown a lack of tissue corresponding to the body and tail of the pancreas,
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along with a slightly atrophic pancreatic head.7 This is in keeping with agenesis of the dorsal
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pancreas, the embryonic structure that gives rise to the pancreatic body, tail and a small part of the
11
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head. Two cases of complete pancreatic agenesis have been described in fetuses terminated for
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severe renal abnormalities and subsequently found to have an HNF1B gene anomaly.1, 57
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Most of these patients also have subclinical pancreatic exocrine dysfunction as evidenced by faecal
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elastase deficiency.6, 7 More detailed assessment using rapid endoscopic secretin tests and secretin-
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stimulated MRI confirms this finding of decreased pancreatic exocrine function in HNF1B-related
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disease.58 Pancreatic exocrine hypersecretion was also seen and may be a compensatory mechanism
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for diminished pancreatic volume, suggesting that the small pancreas of individuals with HNF1B
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mutations is due to hypoplasia rather than atrophy.
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Genital tract malformations
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Genital malformations were described in some of the first cases of HNF1B-related disease, providing
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an early clue that this was a multi-system disorder.8 They are more common in females and are
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usually due to abnormalities in uterine development.26 In a cohort of 108 women with congenital
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uterine abnormalities, a heterozygous mutation or deletion of the HNF1B gene was found in 9 (18%)
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of 50 patients who had both uterine and renal abnormalities, but in none of the 58 cases with
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isolated uterine abnormalities.59 In the female embryo, the Müllerian ducts develop into the
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principal genital duct; Müllerian duct aplasia results in rudimentary uterus and vaginal aplasia.8 The
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corpus and cervix of the uterus plus upper third of the vagina are formed by fusion of the caudal
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parts of the Müllerian ducts; failure of fusion results in bicornuate uterus, uterus didelphys and
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double vagina.33, 60 HNF1B is also a candidate gene for Mayer-Rokitansky-Küster-Hauser syndrome,
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which involves congenital aplasia of the uterus, cervix and upper vagina with primary amenorrhoea
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and infertility.61,
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(cryptorchidism, agenesis of the vas deferens, hypospadias, epididymal cysts and asthenospermia)6,
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25, 33
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with HNF1B-related disease is unclear.
62
A variety of genital tract malformations have been reported in males
; however, as only very small numbers have been identified the significance of this association
12
220
Abnormal liver function tests
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Liver dysfunction was reported in association with HNF1B gene mutations from the earliest
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publications describing the disease.9 It is a frequent finding6,
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asymptomatic rise in liver enzymes, particularly alanine aminotransferase and γ-glutamyl
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transferase.26 At the other end of the spectrum, four patients have presented with neonatal
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cholestasis; liver biopsy shows a reduction of intrahepatic bile ducts.21,
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phenotype is in keeping with the paucity of bile ducts seen in mice with a liver-targeted deletion of
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the HNF1B gene.66 Electron microscopy has recently demonstrated a lack or absence of normal
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primary cilia on bile duct epithelial cells in individuals with HNF1B mutations and this may also result
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in cholestasis.67
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Other clinical features
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There has been recent interest in whether HNF1B gene anomalies are associated with
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neurodevelopmental disorders. A 1.4 Mb deletion at chromosome 17q12, which includes the HNF1B
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gene, was found in 18/15,749 patients referred for clinical genetic testing because of autism
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spectrum disorders, developmental delay and/or cognitive impairment.68 Seizures, structural brain
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abnormalities, mild facial dysmorphic features and macrocephaly have also been reported.68, 69 The
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deleted interval contains 14 other genes alongside HNF1B; currently, it is not clear what mechanism
237
gives rise to this neurodevelopmental phenotype. In a small cohort of 53 children with HNF1B
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whole-gene deletion and cystic kidney disease, three had a diagnosis of autism. This was more
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common than the 1/150-1/300 prevalence of autism seen in the general paediatric population and
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suggests further work is needed in this area to ascertain the exact incidence in this group of
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patients70. Therefore, nephrologists should be aware of this potential association so referral to
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psychiatric services can be made if appropriate.
13
25
and usually manifests as an
63-65
This infrequent
243
Early development of hyperparathyroidism may be a previously unrecognised feature of HNF1B-
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related disease. PTH levels deemed inappropriately high given the degree of renal impairment have
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been reported in 6/11 unselected patients with known HNF1B gene anomalies under follow-up at
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one centre. Five of these six patients had hypomagnesaemia, which usually inhibits PTH release,
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whereas their plasma calcium and phosphate levels were within the normal range. Further work
248
demonstrated that HNF1B is an inhibitor of human PTH gene transcription; HNF1B mutants lacked
249
this repressive property.71
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Other rare clinical features have been reported in very small numbers of individuals with an HNF1B
251
mutation but it is not possible at present to establish a causal link with HNF1B gene anomalies.
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253
Molecular genetics
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HNF1B is a member of the homeodomain-containing superfamily of transcription factors,
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functioning either as a homodimer or as a heterodimer with HNF1A. The HNF1B gene is located on
256
chromosome 17q12 and has three distinct domains: the dimerization domain, the DNA binding
257
domain and the transactivation domain (Figure 2). Genetic changes consist of base substitutions or
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small insertions/deletions in 24/58 (41%) adult patients and 51/116 (44%) affected children/foetuses
259
whereas whole-gene deletions account for 34/58 (59%) adult patients and 65/116 (56%) affected
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children/foetuses.1-3, 11, 20-22, 24, 25, 59, 65
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Over 50 different HNF1B mutations have now been reported, including missense, nonsense,
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frameshift and splicing mutations (Figure 2). Mutations cluster in the first four exons, particularly 2
263
and 4, and the intron 2 splice site also seems to be a mutational hotspot.26 Neither the type nor
264
position of the mutations seems to be associated with a particular phenotype23. Clinical features can
265
vary considerably between both family members and families with the same mutation. This may
14
266
result from other genetic and/or environmental modifiers or stochastic variation resulting from
267
minor differences in temporal expression in early development.
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Whole-gene deletions were identified later. This region of chromosome 17 is susceptible to genomic
269
rearrangement, which is mediated by non-allelic homologous recombination between segmental
270
duplications flanking a 1.5-Mb region.72 These types of genomic rearrangement are not detected by
271
conventional direct sequencing techniques and require gene dosage analysis; however, this will be
272
facilitated by the increasing use of next generation sequencing technology. Deletion of a single exon
273
has also been reported.73
274
Coding region/splice site mutations and whole-gene deletions of HNF1B seem to result in a similar
275
phenotype and this is consistent with haploinsufficiency as the underlying disease mechanism.22, 73
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HNF1B-related disease is classically associated with autosomal dominant inheritance. However, both
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coding region/splice site mutations and whole-gene deletions can arise spontaneously.21, 23 Indeed,
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the prevalence of spontaneous HNF1B gene deletion is reported to be as high as 50%.20 This is
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important as it means there is often no family history of renal disease or diabetes. Whereas the high
280
frequency of de novo deletions is explained by the presence of flanking segmental duplications, the
281
increased rate of spontaneous mutations is likely to arise as a result of the decreased biological
282
fitness of affected individuals.72 Genital tract malformations are seen in HNF1B-related disease,
283
which can result in reduced fertility, and the disorder is associated with wide phenotypic variability,
284
which may not be compatible with life.8, 32
285
Functional studies
286
Organogenesis of several organs is conserved between mammals and zebrafish, making the latter a
287
convenient system for studying renal organogenesis. An insertional mutagenesis screen in zebrafish
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isolated three mutant alleles of vhnf1, the zebrafish homologue of HNF1B. The mutants showed
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formation of renal cysts plus underdevelopment of the pancreas and liver.74
15
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The Xenopus system can also be used to study development of the pronephros, which is the
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functional kidney throughout larval development. Nine different HNF1B mutations, associated with a
292
variety of renal phenotypes in humans, have been compared. In vitro analysis shows that seven of
293
these mutants fail to bind DNA whereas two have an intact DNA-binding domain and bind DNA
294
efficiently. Intact DNA binding correlates with the ability to form dimers and transactivate a reporter
295
gene in transfected cell lines. These mutants all interfere with pronephros development to differing
296
degrees when introduced into Xenopus embryos. The pattern of pronephros development seen in
297
the developing embryo does not strictly correlate with the properties observed in vitro or in
298
transfected cell lines, suggesting that functional studies in Xenopus may define features of the
299
HNF1B transcription factor that are not detected in cell cultures.75
300
Eight further pathogenic mutations located in different domains of the HNF1B protein have been
301
characterised. Findings suggest that disease arises from either impaired DNA-binding or
302
transactivation function through reduced coactivator recruitment (CREB-binding protein and
303
p300/CBP-associated factor).76
304
Despite the presence of a mutational hotspot at the intron 2 splice site, it was initially difficult to
305
investigate the effect of these HNF1B mutations at the mRNA level due to the problem of accessing
306
tissues with high levels of native HNF1B expression. This has been overcome by using ectopically-
307
expressed HNF1B transcripts from Epstein-Barr virus-transformed lymphoblastoid cell lines. This
308
technique has been used to demonstrate how two mutations of the intron 2 splice donor site result
309
in the deletion of exon 2 and are predicted to cause premature termination of the HNF1B protein.77
310
Comparable levels of mRNA transcripts have been demonstrated in both renal tubule cells isolated
311
from a patient’s overnight urine and lymphoblastoid cells, confirming that cell lines provide a good
312
model for mRNA analysis.78
313
16
314
The role of HNF1B in renal development
315
HNF1B is widely expressed in multiple fetal tissues and is required for visceral endoderm
316
specification.79 HNF1A is expressed later than HNF1B and is activated only during organogenesis.80 In
317
adult animals, these transcription factors are expressed in the liver, kidney, pancreatic islets,
318
stomach and intestine; HNF1B is expressed predominantly in the kidney and HNF1A in the liver.
319
HNF1B alone is also expressed in the gonads, thymus and lungs.54 Despite the high degree of
320
homology between these two transcription factors and the fact that they share a common binding
321
site15, HNF1B mutations result in a multi-system disease whereas HNF1A mutations cause MODY.
322
This phenotypic variation is likely a reflection of the different timings and sites of expression of
323
HNF1A and HNF1B during development.
324
Kidney development depends on appropriate interaction between the ureteric bud and metanephric
325
mesenchyme; the former gives rise to the ureter, renal pelvis and collecting duct whereas the latter
326
gives rise to the nephron.81 Renal development starts with induction of the ureteric bud from the
327
nephric duct following signals from the adjacent metanephric mesenchyme. The renal collecting
328
system is formed by invasion of the ureteric bud into the metanephric mesenchyme, with
329
subsequent elongation and branching. Groups of mesenchymal cells near the ureteric bud tips form
330
pretubular aggregates, which differentiate first into comma- and S-shaped bodies, and finally into
331
Bowman’s capsule and tubules.82 The exact role of HNF1B in this complex process is incompletely
332
understood. In situ hybridisation in humans has shown that HNF1B mRNA is detected in fetal
333
collecting ducts, with lower levels of expression in the metanephric mesenchyme.83 Recent work
334
suggests that HNF1B plays an important role in the early stages of urogenital development. The
335
absence of HNF1B in the ureteric bud results in abnormal ureteric bud branching plus a failure of
336
surrounding mesenchymal cells to transition into epithelia, a key step in early nephrogenesis. HNF1B
337
seems to act upstream of Wnt9b and alter Wnt signalling, a pathway known to be crucial in early
338
renal development.84, 85
17
339
Animal models for Hnf1b deficiency have been studied to examine the role of HNF1B during
340
development. Germline inactivation of Hnf1b in mouse embryos is lethal, with death at day 6.5-7.0
341
post-conception.79 Renal-specific inactivation of the HNF1B gene in mice produces animals with
342
polycystic kidneys. This is associated with a marked reduction in the transcriptional activation of the
343
cystic disease genes Umod, Pkhd1 and Pkd2. HNF1B binds to DNA elements in these genes.43 Further
344
work also suggests a link between HNF1B and PKHD1 during kidney development. Transgenic mice
345
expressing a dominant-negative HNF1B mutant under the control of a kidney-specific promoter
346
develop renal cysts; the cells lining these cysts lack the Pkhd1 transcripts that are present in
347
surrounding morphologically normal tubules.86
348
HNF1B is thought to have a role in tubular development within the nephron. In mice, inactivation of
349
Hnf1b in metanephric mesenchyme leads to the formation of aberrant nephrons characterised by
350
glomeruli with a dilated Bowman’s space directly connected to collecting ducts via a primitive
351
tubule; this is due to absence of the proximal and distal tubules plus loop of Henle. This lack of
352
HNF1B also results in deformed S-shaped bodies with no typical bulge of epithelial cells in the mid-
353
limb, which usually gives rise to the proximal tubule and loop of Henle. This phenotype seems to be
354
associated with defective Ixr1, Osr2 and Pou3f3 gene expression plus abnormal Notch signalling
355
activation.87 The Notch signalling pathway is known to be important in tubular segmentation and
356
glomerular formation.88
357
358
Areas for future research
359
As HNF1B-related disease was first described in 1997, many research opportunities still exist in this
360
area. Most cases are referred for genetic testing on account of kidney disease, creating a significant
361
problem with referral bias. Similarly, many of the patient cohorts used to describe the phenotype
362
have been pre-selected for particular renal abnormalities. In view of the intra-familial variability in
18
363
clinical features that is seen, it will be important to systematically collect phenotypic information
364
from all affected family members as well as the proband.
365
The prevalence of HNF1B gene anomalies in the general population is unknown and it is likely that
366
many cases remain undetected due to the variable phenotype and frequency of de novo gene
367
deletions. Recent work identified three individuals with an HNF1B deletion from a group of 258
368
patients who met clinical criteria for MODY and were not known to have renal disease. Although
369
gene mutations were not looked for in this study, they are usually seen at a similar frequency to
370
deletions so an additional three cases would be predicted to harbour an HNF1B coding region/splice
371
site mutation.19 This highlights the need for a better method of selecting patients for genetic testing
372
so the condition can be recognised and treated appropriately. Faguer et al. have recently described
373
an HNF1B score to be used as part of an algorithm for diagnosing HNF1B-related disease. This was
374
created using a weighted combination of the most discriminative clinical features based on the
375
frequency and specificity in the published literature and requires validation in prospective studies in
376
different populations.89
377
Recent studies showing a link between large deletions at chromosome 17q12 and
378
neurodevelopmental disorders has led to speculation about the underlying mechanism and whether
379
deletion of the HNF1B gene within this region may be involved. HNF1B gene anomalies have not
380
previously been suspected to affect neural development and function. This will require further
381
investigation in a large cohort of individuals with both HNF1B mutations and deletions as it will have
382
important implications for patient management.
383
Phenotypic variation in HNF1B-related disease remains poorly understood. It is uncertain if this
384
reflects the functional effects of different gene anomalies, stochastic variation resulting from minor
385
differences in temporal expression in early development, genetic modifiers or the contribution of
386
additional neighbouring deleted genes in those patients with the common 1.5-Mb deletion that
19
387
includes HNF1B. Comparing large groups of patients with both extreme phenotypic variation and
388
whole-gene deletions versus coding region/splice site mutations may help identify some of the
389
determinants of this varied phenotype. It will also be important to establish a prospective paediatric
390
cohort as the follow-up of affected children will allow the development and evolution of different
391
clinical features to be studied.
392
393
Conclusions
394
HNF1B first generated interest in 1997 as a potential candidate gene for MODY; it is now known to
395
be the most common monogenic cause of developmental renal disease. Mutations result in a
396
multisystem disorder and recent work has suggested that neurodevelopmental features, such as
397
autism spectrum disorders, may be part of the phenotype in individuals with whole-gene deletions.
398
HNF1B-related disease is characterised by marked clinical heterogeneity and a positive family history
399
is often lacking. As a result, many cases are likely to have been missed. Further work is needed to
400
improve identification of appropriate patients for genetic testing and understand this phenotypic
401
variation. HNF1B genetic testing should be considered in patients with developmental renal disease,
402
particularly if renal cysts/hyperechogenicity are detected or other extra-renal clinical features are
403
present.
404
405
Review criteria
406
The PubMed database was searched using the following search terms: “maturity onset diabetes of
407
the young type 5”, “renal cysts and diabetes syndrome”, “hepatocyte nuclear factor 1 beta”,
408
“transcription factor 2”, “HNF1beta”, “HNF1B”, “TCF2”, “MODY5” and “RCAD”. Other references are
409
derived from the authors’ knowledge of the published literature. The search was restricted to
20
410
articles published in English and focused on papers published from January 1997 to June 2014,
411
although relevant articles published before 1997 were also included.
412
413
Key points
414
1. Heterozygous mutations in the gene encoding the transcription factor HNF1B result in a multi-
415
system disorder and are the most common known monogenic cause of developmental renal disease.
416
2. The renal phenotype is extremely variable; cysts are the most frequent feature but single kidneys,
417
hypoplasia, horseshoe kidneys, duplex kidneys, collecting system abnormalities, bilateral
418
hydronephrosis and hyperuricaemic nephropathy are also seen.
419
3. HNF1B-related disease is often detected on prenatal ultrasound scanning, where the most
420
common phenotype seen before birth is isolated bilateral hyperechogenic kidneys with normal or
421
slightly increased size.
422
4. Electrolyte abnormalities include hypomagnesaemia and hyperuricaemia; extra-renal phenotypic
423
features include young-onset diabetes, pancreatic hypoplasia, genital tract malformations and
424
deranged liver function tests..
425
5. Genetic changes consist of base substitutions or small insertions/deletions in approximately 50%
426
of patients and whole-gene deletions in the remainder; there is currently no evidence for a
427
genotype-phenotype correlation.
428
6. Although often associated with autosomal dominant inheritance, both mutations and whole-gene
429
deletions can arise spontaneously which means there may be no family history of renal disease or
430
diabetes.
431
432
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Acknowledgements
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R Clissold is supported by a Medical Research Council Clinical Training Fellowship. A Hattersley is a
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National Institute for Health Research Senior Investigator. S Ellard and A Hattersley are supported by
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Wellcome Trust Senior Investigator awards. The authors would like to thank Kevin Colclough, clinical
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scientist at Exeter Molecular Genetics Laboratory, for his assistance with Figure 2.
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The authors declare no competing interests.
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