Lec:3
Dr.Mohammed Alhamdany
Presenting Problems in Genetic Disease
Common monogenic disorders affecting major organ
systems:
1-Multisystem: Neurofibromatosis AD ,Tuberous sclerosis AD
2-Respiratory 1-antitrypsin deficiency AR, Cystic fibrosis AR
3-Cardiovascular: Hypertrophic cardiomyopathy AD, Long QT
syndromes AD and AR
4-Renal: Polycystic kidney disease AD ,Alport’s syndrome XLR
Gastrointestinal:
Hereditary
pancreatitis
AD
,Familial
adenomatous polyposis coli AD
5-Hepatic: Gilbert’s disease AD ,Haemochromatosis AR
,Wilson’s disease AR
6-Metabolic:
Phenylketonuria
AR
,
Familial
hypercholesterolaemia AD
7-Endocrine: Congenital adrenal hyperplasia AR ,Multiple
endocrine neoplasia AD ,Kallmann’s syndrome XLR or AD
8-Haematological: Sickle-cell disease AR, Alpha- and betathalassaemia AR, Haemophilia A and B XLR
9-Neuromuscular: Duchenne muscular dystrophy XLR, Myotonic
dystrophy AD,Spinal muscular atrophy AR.
10-CNS: Huntington’s disease AD ,Familial Alzheimer’s disease
AD, Friedreich’s ataxia AR
11-Musculoskeletal: Ehlers–Danlos syndrome AD, Marfan’s
syndrome AD ,Osteogenesis imperfecta AD and AR
12-Skin: Albinism AR ,Neurofibromatosis AD ,Xeroderma
pigmentosum AR
13-Eye: Retinitis pigmentosa AR, AD, XLR ,Ocular albinism XLR
Familial cancer syndromes
1-Retinoblastoma: Patients with autosomal dominant familial retinoblastoma
have an inherited mutation in one copy of the RB gene, which is a tumour
suppressor. This strongly predisposes individuals to the formation of
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retinoblastoma in one or both eyes, there is an increased incidence of osteogenic
sarcoma.
2-Familial adenomatous polyposis coli: Familial adenomatous polyposis coli
(FAP) is an autosomal dominant condition due to inactivation mutations in the
FAP tumour suppressor gene on 5q. Mutation carriers usually develop many
thousands of intestinal polyps in their second and third decades and have a very
high risk of malignant change in the colon. Prophylactic colectomy in the third
decade is necessary in most cases. Regular screening for polyps in the upper
gastrointestinal tract is also recommended.
3-Hereditary non-polyposis colorectal cancer (HNPCC): is an autosomal
dominant disorder that presents with early onset familial colon cancer, particularly
affecting the proximal colon. Other cancers, such as endometrial cancer, are often
observed in affected families.
4-Familial breast cancer: Familial breast cancer is an autosomal dominant
disorder that is most often due to mutations in genes encoding either BRCA1 or
BRCA2. Both these proteins are involved in DNA repair. Individuals who carry a
BRCA1 or BRCA2 mutation are at high risk of early-onset breast and ovarian
tumours, and require regular screening for both these conditions. Many affected
women will opt for prophylactic bilateral mastectomy and oophorectomy.
5-Peutz–Jeghers syndrome: AD disease affect gastrointestinal, endometrial,
breast, ovary.
6-Werner’s syndrome: Werner’s syndrome is a form of premature ageing
(progeria), caused by mutation of one of a series of DNA repair enzymes; it
presents with premature skin ageing, degenerative disorders and cancer.
Research Frontiers in Molecular Medicine:
Stem cell therapy and regenerative medicine
The identification of adult stem cells and the ability to purify and maintain such
cells in vitro offer very exciting therapeutic potential . Indeed, adult stem cell
therapy has been in wide use for decades in the form of bone marrow
transplantation. The recent discovery that adult fibroblasts can be
transdifferentiated to form cells with almost all the characteristics of embryonal
stem cells derived from the early blastocyst has negated much of the controversy
surrounding this approach to therapy. In mammalian model species, such cells can
be taken and used to regenerate differentiated tissue cells, such as in heart and
brain. They have the ability to produce any cell in the body and proliferate rapidly
in culture, and so could be used to refashion damaged organs. Such experiments
are still in their infancy but are progressing fast.
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Polymorphisms
A polymorphism is defined as one that exists with a population frequency of > 1%.
Most common polymorphisms are neutral, but some cause subtle changes in gene
expression or in protein structure and function .It is thought that these
polymorphisms lead to variations in phenotype within the general population,
including variations in susceptibility to common diseases. An example is
polymorphism in the gene HFE with genetic variant include (C282Y) in 3% of
population and (H63D) in 5% of population that predispose the patient for
Haemochromatosis(AR).
Neutral variants
The vast majority of variations within the human genome have no effect on the cell
or organism. This may be because 1- the variation lies within an intron of a gene or
a region of the genome which does not code for a gene or a regulatory element.
Also,2- some variations within the coding regions of a gene do not change the
amino acid, typically when the third base of a codon is affected. 3-Some variations
that do change the amino acid result in a conservative substitution, which does not
change protein function appreciably.
Genotype and Phenotype
An observed feature is referred to as a phenotype ; the genetic information defining
the phenotype is called the genotype . Alternative forms of a gene or a genetic
marker are referred to as alleles. The normal or common allele is usually referred
to as wild type. When alleles at a given locus are identical, the individual is
homozygous . Inheriting identical copies of a mutant allele occurs in many
autosomal recessive disorders, particularly in circumstances of consanguinity. If
the alleles are different on the maternal and the paternal copy of the gene, the
individual is heterozygous at this locus. If two different mutant alleles are inherited
at a given locus, the individual is said to be a compound heterozygote. Hemizygous
is used to describe males with a mutation in an X chromosomal gene or a female
with a loss of one X chromosomal locus.
Allelic heterogeneity
Allelic heterogeneity is the term given to the phenomenon in which several
different mutations cause the same phenotype. In familial adenomatous
polyposis coli, whole gene deletions, nonsense mutations, frameshift
mutations and some missense mutations result in exactly the same
phenotype because they all cause loss of function in the FAP gene on
chromosome 5q. Many other Mendelian disorders show this phenomenon
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with loss-of-function mutations, including adult polycystic kidney disease
(PKD1, PKD2).
Locus heterogeneity
Locus heterogeneity is the term given to the phenomenon whereby a
similar phenotype results from mutations in several different genes. One of
the best examples is retinitis pigmentosa, which can occur as the result of
mutations in more than 75 genes, each of which has a different
chromosomal location.
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