SEMA3A – SEMA3A Variants in Kallmann Syndrome

Kallmann syndrome (KS) is characterized by hypogonadotropic hypogonadism and anosmia due to defective migration of GnRH neurons. SEMA3A encodes semaphorin-3A, a secreted axon guidance cue that signals via Neuropilin-1/PlexinA receptors to direct olfactory and GnRH neuron development.

In a cohort of 386 KS patients screened by Sanger sequencing, 24 heterozygous SEMA3A variants—including a frameshift and seven distinct missense changes—were identified, all impairing secretion or signaling in COS-7 and GN11 cell assays ([PMID:22927827]). Three additional heterozygous missense variants were found in 3 of 34 Finnish KS patients, although two occurred alongside FGFR1 mutations, suggesting a modifier role ([PMID:24522099]).

A Chinese family study reported a novel heterozygous c.814G>T (p.Asp272Tyr) variant in two affected members; bioinformatics predicted structural disruption, and in vitro assays showed reduced SEMA3A expression and failure to induce FAK phosphorylation in GnRH neurons ([PMID:36267363]).

Further screening in Chinese IHH cohorts identified the V458I variant in one KS patient and R197Q/R617Q in normosmic IHH. All three mutants exhibited impaired FAK phosphorylation and GN11 cell migration; V458I additionally showed secretion defects ([PMID:32060892]).

In vivo, Nrp1(sema/sema) mice lacking semaphorin-binding capacity phenocopy KS, with olfactory system maldevelopment and failed GnRH cell migration, underscoring semaphorin-3A haploinsufficiency as a pathogenic mechanism ([PMID:22927827]).

SEMA3A heterozygous variants thus contribute to KS via a dominant haploinsufficiency mechanism, often in an oligogenic context with FGFR1, ANOS1, or CHD7, resulting in variable penetrance. Genetic testing for SEMA3A should be considered in KS diagnostic panels, with functional assays guiding variant interpretation.

Key Take-home: Heterozygous loss-of-function SEMA3A variants confer strong risk for KS through impaired GnRH neuron guidance, supporting its inclusion in clinical genetic testing.

References

• PLoS Genetics • 2012 • SEMA3A, a gene involved in axonal pathfinding, is mutated in patients with Kallmann syndrome. PMID:22927827
• Pediatric Research • 2014 • Mutation screening of SEMA3A and SEMA7A in patients with congenital hypogonadotropic hypogonadism. PMID:24522099
• Clinical Genetics • 2020 • Functional analysis of SEMA3A variants identified in Chinese patients with isolated hypogonadotropic hypogonadism. PMID:32060892
• International Journal of Endocrinology • 2022 • Identification and Functional Characterization of a Novel Variant in the SEMA3A Gene in a Chinese Family with Kallmann Syndrome. PMID:36267363

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