CCDC141 Mutation Identified in Anosmic Hypogonadotropic Hypogonadism (Kallmann Syndrome) Alters GnRH Neuronal Migration

Abstract

The first mutation in a gene associated with a neuronal migration disorder was identified in patients with Kallmann Syndrome, characterized by hypogonadotropic hypogonadism and anosmia. This pathophysiological association results from a defect in the development of the GnRH and the olfactory system. A recent genetic screening of Kallmann Syndrome patients revealed a novel mutation in CCDC141. Little is known about CCDC141, which encodes a coiled-coil domain containing protein. Here, we show that Ccdc141 is expressed in GnRH neurons and olfactory fibers and that knockdown of Ccdc141 reduces GnRH neuronal migration. Our findings in human patients and mouse models predict that CCDC141 takes part in embryonic migration of GnRH neurons enabling them to form a hypothalamic neuronal network to initiate pulsatile GnRH secretion and reproductive function.

Mutation profiles and clinical characteristics of Chinese males with isolated hypogonadotropic hypogonadism

“…This result may be explained in part by the limited number of genes included in the study. Recently, more genes, such as CCDC141 and FEZF1, have been reported to cause IHH (48,49). These genes may explain some of the unknown genetic causes of IHH.…”

A novel GNRHR gene mutation causing congenital hypogonadotrophic hypogonadism in a Brazilian kindred

“…It has been shown that CCDC141 is present in migrating GnRH neurones and in olfactory axons in mice. Knockdown mice models have shown a decrease in GnRH axon movement and migration but have not affected olfactory axon outgrowth . It has been suggested that variants in cytoskeleton‐associated genes, such as CCDC141 , may be found as secondary mutations in CHH contributing to impaired neuronal migration .…”

“…Knockdown mice models have shown a decrease in GnRH axon movement and migration but have not affected olfactory axon outgrowth. 36 It has been suggested that variants in cytoskeleton-associated genes, such as CCDC141, may be found as secondary mutations in CHH contributing to impaired neuronal migration. 35 We are unable to state for certain that these heterozygous missense variants in CCDC141 found in WES have any role in modifying GNRHR phenotype in the CHH proband.…”

Update on the Genetics of Idiopathic Hypogonadotropic Hypogonadism

“…Furthermore, there may be pathophysiological overlaps between the two entities. For example, patients with CCDC141 or IGSF10 mutations have nIHH despite showing in vitro evidence of impaired migration of the GnRH neurons ( 3 , 4 ).…”