Analysis of mutations in patients with Kallmann syndrome

doi:10.3969/j.issn.1006-7795.2014.06.017

Abstract

Abstract:

Objective To analyze the mutation of Kallmann syndrome 1(KAL1), prokineticin(PROK2) and prokineticin receptor 2(PROKR2) in a family, which has a 13-year-old son with Kallmann syndrome(KS). Methods ① Hormone levels were measured by immunoradiometric assay, abdomen structures were assessed by abdominal ultrasound scan, brain magnetic resonance imaging(MRI) was used to visualize the olfactory bulbs, sulci, and inner ears; ② The exon sequences of the three genes(KAL1, PROK2 and PROKR2) were screened for a mutation by direct sequencing; ③ SIFT, Polyphen and MutationTaster were used as a complementary approach to assess the significance of polymorphisms and missense mutations. Results ① The patient had sexual infantilism, and the MRI of the head revealed the dysplasia of olfactory bulbs and olfactory tract; the parents of this patient had normal pubertal development, serum gonadotropin and estradiol concentrations, and their MRI results showed normal olfactory bulbs; ② In KAL1 gene, two novel mutations(I565T and S570T) and five previously described polymorphisms(V534I, V560F, G567S, K666M and R668H) were detected in this patient. In PROKR2 gene, a homozygous Y113H was presented in this patient, and this mutation was also detected in the heterozygous state in his parents; ③ I565T, Y113H (PROKR2) and S570T may be the harmful variation according to our stringent analysis. Conclusion To date, these two novel mutations have not yet been reported in the Chinese population, and this is the first case of KS patient who exhibited two-point mutation in KAL1 and was also carried a missense mutation in PROKR2, thus indicating a possible digenic inheritance of the disease in this individual.

Key words: Kallmann syndrome, KAL1, PROKR2, mutation

CLC Number:

R588

Cao Xi, Xie Rongrong, Xin Zhong, Yang Jinkui. Analysis of mutations in patients with Kallmann syndrome[J]. Journal of Capital Medical University, 2014, 35(6): 765-770.

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URL: https://journal03.magtech.org.cn/Jweb_sdykdxxb/EN/10.3969/j.issn.1006-7795.2014.06.017

https://journal03.magtech.org.cn/Jweb_sdykdxxb/EN/Y2014/V35/I6/765

References

[1] Hu Y, Tanriverdi F, MacColl G S, et al. Kallmann's syndrome: molecular pathogenesis[J]. Int J Biochem Cell Biol, 2003,35(8):1157-1162.
[2] Fechner A, Fong S, McGovern P. A review of Kallmann syndrome: genetics, pathophysiology, and clinical management[J]. Obstet Gynecol Surv, 2008,63 (3):189-194.
[3] Ribeiro R S, Vieira T C, Abucham J. Reversible Kallmann syndrome: report of the first case with a KAL1 mutation and literature review[J]. Eur J Endocrinol, 2007,156(3):285-290.
[4] Franco B, Guioli S, Pragliola A, et al. A gene deleted in Kallmann's syndrome shares homology with neural cell adhesion and axonal path-finding molecules[J]. Nature, 1991,353(6344):529-536.
[5] Dode C, Levilliers J, Dupont J M, et al. Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome[J]. Nat Genet, 2003,33(4):463-465.
[6] Falardeau J, Chung W C, Beenken A, et al. Decreased FGF8 signaling causes deficiency of gonadotropin-releasing hormone in humans and mice[J]. J Clin Invest, 2008,118(8):2822-2831.
[7] Pitteloud N, Zhang C, Pignatelli D, et al. Loss-of-function mutation in the prokineticin 2 gene causes Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism[J]. Proc Natl Acad Sci U S A, 2007,104(44):17447-17452.
[8] Dode C, Teixeira L, Levilliers J, et al. Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2[J]. PLoS Genet, 2006,2(10):e175.
[9] Kim H G, Ahn J W, Kurth I, et al. WDR11, a WD protein that interacts with transcription factor EMX1, is mutated in idiopathic hypogonadotropic hypogonadism and Kallmann syndrome[J]. Am J Hum Genet, 2010,87(4):465-479.
[10] Tsai P S, Gill J C. Mechanisms of disease: Insights into X-linked and autosomal-dominant Kallmann syndrome[J]. Nat Clin Pract Endocrinol Metab, 2006,2(3):160-171.
[11] Ng P C, Henikoff S. SIFT: Predicting amino acid changes that affect protein function[J]. Nucleic Acids Res, 2003,31(13):3812-3814.
[12] Adzhubei I A, Schmidt S, Peshkin L, et al. A method and server for predicting damaging missense mutations[J]. Nat Methods, 2010,7(4):248-249.
[13] Schwarz J M, Rodelsperger C, Schuelke M, et al. MutationTaster evaluates disease-causing potential of sequence alterations[J]. Nat Methods, 2010,7(8):575-576.
[14] Kim S H, Hu Y, Cadman S, et al. Diversity in fibroblast growth factor receptor 1 regulation: learning from the investigation of Kallmann syndrome[J]. J Neuroendocrinol, 2008,20(2):141-163.
[15] Tsuge T, Shimokawa T, Horikoshi S, et al. Polymorphism in promoter region of Fcalpha receptor gene in patients with IgA nephropathy[J]. Hum Genet, 2001,108(2):128-133.
[16] Yamada R, Tanaka T, Unoki M, et al. Association between a single-nucleotide polymorphism in the promoter of the human interleukin-3 gene and rheumatoid arthritis in Japanese patients, and maximum-likelihood estimation of combinatorial effect that two genetic loci have on susceptibility to the disease[J]. Am J Hum Genet, 2001,68(3):674-685.
[17] Cole L W, Sidis Y, Zhang C, et al. Mutations in prokineticin 2 and prokineticin receptor 2 genes in human gonadotrophin-releasing hormone deficiency: molecular genetics and clinical spectrum[J]. J Clin Endocrinol Metab, 2008,93(9):3551-3559.
[18] Badano J L, Katsanis N. Beyond Mendel: an evolving view of human genetic disease transmission[J]. Nat Rev Genet, 2002,3(10):779-789.
[19] Carlton V E, Harris B Z, Puffenberger E G, et al. Complex inheritance of familial hypercholanemia with associated mutations in TJP2 and BAAT[J]. Nat Genet, 2003,34(1):91-96.
[20] Pitteloud N, Quinton R, Pearce S, et al. Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism[J]. J Clin Invest, 2007,117(2):457-463.
[21] Gonzalez-Martinez D, Kim S H, Hu Y, et al. Anosmin-1 modulates fibroblast growth factor receptor 1 signaling in human gonadotropin-releasing hormone olfactory neuroblasts through a heparan sulfate-dependent mechanism[J]. J Neurosci, 2004,24(46):10384-10392.
[22] Dode C, Hardelin J P. Kallmann syndrome: fibroblast growth factor signaling insufficiency?[J]. J Mol Med(Berl), 2004,82(11):725-734.
[23] Gao Y Q, Danciger M, Ozgul R K, et al. Association of the Asn306Ser variant of the SP4 transcription factor and an intronic variant in the beta-subunit of transducin with digenic disease[J]. Mol Vis, 2007,13:287-292.
[24] Muntoni F, Bonne G, Goldfarb L G, et al. Disease severity in dominant Emery Dreifuss is increased by mutations in both emerin and desmin proteins[J]. Brain, 2006,129(Pt 5):1260-1268.
[25] Tosch V, Rohde H M, Tronchere H, et al. A novel PtdIns3P and PtdIns(3,5) P2 phosphatase with an inactivating variant in centronuclear myopathy[J]. Hum Mol Genet, 2006,15(21):3098-3106.