Supplementary table 4
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Supplementary table 4. Exon Nucleotide change PROKR2 1 58del PROKR2 and PROK2 mutations in Kallmann syndrome PROKR2 and PROK2 mutations in Kallmann syndrome Aminoacid Localization (domain) Expected change consequence Frameshift N-terminal region NMD or protein truncation G proteincoupling defect? G proteincoupling defect? G proteincoupling defect? G proteincoupling defect? ? ? NMD or protein truncation G proteincoupling defect? 238C>T R80C First intracellular loop - 253C>T† R85C First intracellular loop - 254G>T R85L First intracellular loop - 254G>A R85H First intracellular loop - 337T>C 343G>A 420C>G Y113H V115M Y140X First extracellular loop First extracellular loop Third transmembrane domain 2 491G>A R164Q Second intracellular loop - 518T>G L173R Fourth transmembrane domain Cell surface targetingdefect - 533G>C W178S Fourth transmembrane domain Cell surface targetingdefect - 563C>T S188L - 629A>G Q210R Fourth transmembrane domain Second extracellular loop - 743G>A R248Q Third intracellular loop - 802C>T† R268C Third intracellular loop - T820>A V274D Sixth transmembrane domain - 868C>T† P290S Sixth transmembrane domain Ligandbinding defect G proteincoupling defect? G proteincoupling defect? Cell surface targetingdefect? Cell surface targetingdefect References Dodé et al., 2006 Abreu et al., 2008 Cole et al., 2008 Monnier et al., 2008 C. Dodé, unpublished Dodé et al., 2006 Monnier et al., 2008 Cole et al., 2008 Cole et al., 2008 Abreu et al., 2008 Dodé et al., 2006 Cole et al., 2008 Monnier et al., 2008 Dodé et al., 2006 Abreu et al., 2008 Cole et al., 2008 Monnier et al., 2008 Dodé et al., 2006 Cole et al., 2008 Monnier et al., 2008 Cole et al., 2008 Dodé et al., 2006 Monnier et al., 2008 Cole et al., 2008 Dodé et al., 2006 Abreu et al., 2008 Monnier et al., 2008 Sinisi et al., 2008 Dodé et al., 2006 Monnier et al., 2008 - 969G>A M323I Seventh transmembrane domain ? - 991G>A† V331M Seventh transmembrane domain G proteincoupling defect? - 1069C>T R357W C-terminal region G proteincoupling defect? Translation initiation site Reduced protein synthesis Targeting defect Loss of protein activity Disulfide bond loss ? ? PROK2 1 -4C>A - 70G>C A24P Signal peptide - 94G>C G32R AVITGA motif 2 101G>A C34Y Cysteine-rich region - 150C>G 161G>A I50M S54N Cysteine-rich region Cysteine-rich region - 163del Frameshift Cysteine-rich region - 217C>T R73C Cysteine-rich region 4 297_298insT Frameshift Cysteine-rich region - 310C>T H104Y Cysteine-rich region NMD or protein truncation Disulfide bond disruption NMD or protein truncation ? Dodé et al., 2006 Monnier et al., 2008 Dodé et al., 2006 Cole et al., 2008 Monnier et al., 2008 Cole et al., 2008 Dodé et al., 2006 Cole et al., 2008 Dodé et al., 2006 Cole et al., 2008 Cole et al., 2008 C. Dodé, unpublished Pitteloud et al., 2007 Leroy et al., 2008 Dodé et al., 2006 Leroy et al., 2008 Cole et al., 2008 Dodé et al., 2006 Abreu et al, 2008 C. Dodé, unpublished Mutations reported in PROKR2 and PROK2 are mainly missense mutations. In most patients, the mutations have been found in heterozygous state. The p.R85H and p.L173R PROKR2 mutations, as well as p.R73C, c.163del, and c.297_298insT PROK2 mutations, however, have been found both in heterozygous and homozygous (or compound heterozygous) states, which suggests that patients heterozygous for PROKR2 or PROK2 mutations carry additional mutations, presumably in other as yet unidentified Kallmann syndrome genes in most cases. Notably, one such patient has the p.R85L mutation in PROKR2 together with a p.A604T mutation in FGFR1 (C. Dodé, unpublished), another patient has the p.V115M mutation in PROKR2 together with the p.A24P mutation in PROK2 (Cole et al., 2008), and a third patient has the p.L173R mutation in PROKR2 together with a p.S396L mutation in KAL1 (Dodé et al., 2006). † This mutation has also been found in one out of 250 individuals from the general population. Abbreviation: NMD, nonsense-mediated mRNA decay. References Abreu A, Trarbach E, de Castro M, et al. (2008) Loss-of-function mutations in the genes encoding prokineticin-2 or prokineticin receptor-2 cause autosomal recessive Kallmann syndrome. J Clin Endocrinol Metab 10: 4113–4118. Cole LW, Sidis Y, Zhang C, et al. (2008) Mutations in prokineticin 2 (PROK2) and PROK2 receptor (PROKR2) in human gonadotrophin-releasing hormone deficiency: molecular genetics and clinical spectrum. J Clin Endocrinol Metab 93: 3551–3559. Dodé C, Teixeira L, Levilliers J, et al. (2006) Kallmann syndrome: mutations in the genes encoding prokineticin2 and prokineticin receptor-2. PLoS Genet 2: 1648–1652. Monnier C, Dodé C, Fabre L, et al. (2008) PROKR2 missense mutations associated with Kallmann syndrome impair receptor signalling-activity. Hum Mol Genet (in press). Pitteloud N, Zhang C, Pignatelli D, et al. (2007) Loss-of-function mutation in the prokineticin 2 gene causes Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism. Proc Natl Acad Sci U S A 104: 17447–17452. Leroy C, Fouveaut C, Leclercq S, et al. (2008) Biallelic mutations in the prokineticin-2 gene in two sporadic cases of Kallmann syndrome. Eur J Hum Genet 16: 865–868. Sinisi AA, Asci R, Bellastella G, et al. (2008) Homozygous mutation in the prokineticin-receptor 2 gene (Val274Asp) presenting as reversible Kallmann syndrome and persistent oligozoospermia: case report. Hum Reprod 23: 2380–2384.
