CCDC141 – Kallmann syndrome

CCDC141 has been implicated in congenital hypogonadotropic hypogonadism with anosmia (Kallmann syndrome, MONDO:0018800) primarily through functional studies and oligogenic reports rather than independent monogenic segregation. No autosomal recessive families have been reported in which biallelic CCDC141 variants segregate exclusively with KS; instead, a multi-family cohort identified nine affected individuals with inactivating CCDC141 variants presenting normosmic IHH, not anosmia ([PMID:28324054]). A single CCDC141 variant, c.2803C>T (p.Arg935Trp), was involved in digenic combinations in one KS proband in combination with PROKR2 variants, underscoring oligogenic inheritance ([PMID:34539727]).

Functional assays demonstrate that CCDC141 is expressed in GnRH neurons and olfactory fibers, and knockdown in vitro impairs GnRH neuronal migration, recapitulating key features of KS pathophysiology ([PMID:27014940]). However, the lack of clear monogenic segregation, along with evidence that CCDC141 loss predominantly causes normosmic IHH, limits definitive association with KS. Further AR family studies and rescue models are warranted.

Key Take-home: CCDC141 variants disrupt GnRH migration but currently lack robust monogenic evidence to support a standalone autosomal recessive cause of Kallmann syndrome.

References

• Endocrinology • 2016 • CCDC141 Mutation Identified in Anosmic Hypogonadotropic Hypogonadism (Kallmann Syndrome) Alters GnRH Neuronal Migration PMID:27014940
• The Journal of clinical endocrinology and metabolism • 2017 • CCDC141 Mutations in Idiopathic Hypogonadotropic Hypogonadism PMID:28324054
• Frontiers in genetics • 2021 • Oligogenic Inheritance Underlying Incomplete Penetrance of PROKR2 Mutations in Hypogonadotropic Hypogonadism PMID:34539727

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