SEMA3A, a Gene Involved in Axonal Pathfinding, Is Mutated in Patients with Kallmann Syndrome

Abstract

Kallmann syndrome (KS) associates congenital hypogonadism due to gonadotropin-releasing hormone (GnRH) deficiency and anosmia. The genetics of KS involves various modes of transmission, including oligogenic inheritance. Here, we report that Nrp1 sema/sema mutant mice that lack a functional semaphorin-binding domain in neuropilin-1, an obligatory coreceptor of semaphorin-3A, have a KS–like phenotype. Pathohistological analysis of these mice indeed showed abnormal development of the peripheral olfactory system and defective embryonic migration of the neuroendocrine GnRH cells to the basal forebrain, which results in increased mortality of newborn mice and reduced fertility in adults. We thus screened 386 KS patients for the presence of mutations in SEMA3A (by Sanger sequencing of all 17 coding exons and flanking splice sites) and identified nonsynonymous mutations in 24 patients, specifically, a frameshifting small deletion (D538fsX31) and seven different missense mutations (R66W, N153S, I400V, V435I, T688A, R730Q, R733H). All the mutations were found in heterozygous state. Seven mutations resulted in impaired secretion of semaphorin-3A by transfected COS-7 cells (D538fsX31, R66W, V435I) or reduced signaling activity of the secreted protein in the GN11 cell line derived from embryonic GnRH cells (N153S, I400V, T688A, R733H), which strongly suggests that these mutations have a pathogenic effect. Notably, mutations in other KS genes had already been identified, in heterozygous state, in five of these patients. Our findings indicate that semaphorin-3A signaling insufficiency contributes to the pathogenesis of KS and further substantiate the oligogenic pattern of inheritance in this developmental disorder.

Biallelic SEMA3A defects cause a novel type of syndromic short stature

“…Finally, a heterozygous intragenic SEMA3A deletion was recently observed in a father and his two children with signs of Kallmann syndrome (hypogonadotropic hypogonadism and anosmia) and supported by the mouse findings of Cariboni et al [2011] was considered causative . However, a study of SEMA3A mutations in 386 patients with Kallmann syndrome suggested that monoallelic mutations in SEMA3A were not sufficient to induce the abnormal phenotype, but may contribute to the pathogenesis of Kallmann syndrome through synergistic effects with mutant alleles of other disease-associated genes [Hanchate et al, 2012]. Accordingly, neither our compound heterozygous patient nor his heterozygous father had obvious signs of Kallmann syndrome.…”

“…Due to the pivotal role of SEMA3A in development, it was widely studied in a variety of human conditions and heterozygous variants have been associated with Hirschsprung disease [Jiang et al, 2012], with the crypt frequency in human iris patterns [Larsson et al, 2011]; and with hypogonadotropic hypogonadism and anosmia (Kallmann syndrome) [Hanchate et al, 2012;Young et al, 2012].…”

MANAGEMENT OF ENDOCRINE DISEASE: Reversible hypogonadotropic hypogonadism

“…Mutations in genes such as GNRH1, GRNHR, KISS1 or KISS1R (7, 8,9,10,11,12,13,14) can impair the action (or secretion) of GnRH, resulting in normosmic CHH. In contrast, mutations in genes impacting the migration of GnRH neurons from the olfactory placode during development (ANOS1, SEMA3A, IL17RD, SOX10 and FEZF1) (15,16,17,18,19,20,21) result in KS. KAL1, recently renamed ANOS1, was the first X-linked gene implicated in CHH (15,16,22,23).…”

European Consensus Statement on congenital hypogonadotropic hypogonadism—pathogenesis, diagnosis and treatment

“…Genes encoding fibroblast growth factor 8 (FGF8) signalling pathway proteins, [17][18][19][20][21][22] chromodomain helicase DNA-binding protein 7 (CHD7) [23][24][25][26][27] and sex determining region Y-Box 10 (SOX10) 28,29 affect the neurogenic niche in the nasal area and craniofacial development. Conversely, Kallmann syndrome protein, which is now officially known as anosmin 1 (encoded by KAL1; following nomenclature change, the gene is now denoted as ANOS1), 2 prokineticin-2 and prokineticin receptor 2 (encoded by PROK2 and PROKR2, respectively), [30][31][32][33] WD repeat domain 11 (encoded by WDR11), 34,35 semaphorin 3A (encoded by SEMA3A) [36][37][38] and FEZ family zinc finger 1 (encoded by FEZF1) 39 influence migration of GnRH neurons.…”

“…117,118 To date, >25 different genes have been implicated in Kallmann syndrome and/or CHH, which accounts for ~50% of cases. 21 Causative genes for Kallmann syndrome include: KAL1 (ANOS1) in the X-linked form; FGFR1 (encoding fibroblast growth factor receptor 1), 17,18 FGF8, 19,119 CHD7, [23][24][25][26][27] HS6ST1 (encoding heparan-sulphate 6-O-sulphotransferase 1), 20 SOX10, 28,29 SEMA3A (encoding semaphorin-3A), [36][37][38] WDR11 (encoding WD repeat-containing protein 11) 34,35 and IL17RD (encoding interleukin-17 receptor D) 21 in the autosomal dominant form; and PROKR2 and/or PROK2, [30][31][32][33] and FEZF1 39 in the autosomal recessive form, even though it should be noted that most patients carrying mutations in PROKR2 or PROK2 carry these mutations in the heterozygous state. 120,121 Genes involved in CHH that are associated with a normal sense of smell include GNRHR (encoding gonadotropinreleasing hormone receptor), 122,123 GNRH1 (encoding gonadotropin-releasing hormone 1), 124,125 KISS1R, 41,42 KISS1, 40,126 TACR3 and TAC3.…”