Endocrine Abstracts

Kallmann syndrome (KS) is a genetic disorder associating pubertal failure with congenital absent or impaired sense of smell. KS is related to defective neuronal development affecting both the migration of olfactory nerve endings and GnRH neurons. The discovery of several genetic mutations responsible for KS led to the identification of signaling pathways involved in these processes, but the mutations so far identified account for only 30–40% of cases of KS. We attempted to identify new KS responsible genes by using a pangenomic approach and we identified SEMA3A. Thus, from an initial cohort of 120 KS patients, we first studied 48 propositi with no mutations in known KS genes. They were analyzed by CGHarray, using Agilent 105K oligonucleotide chips with a mean resolution of 50 kb. We first found one propositus who had a heterozygous deletion of 213 kb at locus 7q21.11, confirmed by real-time qPCR, deleting 11 of the 17 SEMA3A exons. This deletion co-segregated in the propositus’ family with the KS phenotype. Later, thanks to a French and European network, additional non synonymous heterozygous mutations in 24 patients, a frameshifting small deletion (D538fsX31) and seven different missense loss of function mutations were reported. SEMA3A codes for semaphorin 3A, a protein that interacts with neuropilins. Interestingly, mice lacking semaphorin 3A expression have been showed to have a Kallmann-like phenotype. SEMA3A is therefore a new gene whose loss of function is involved in KS. These findings validate the specific contribution of semaphorin 3A to the development of the olfactory system and in neuronal control of puberty in humans. The mode of inheritance (autosomal dominant or recessive or oligogenic) of this novel genetic form remains to be clearly established in familial and sporadic KS cases. Reproductive phenotypes and gonadotropin axis abnormalities in SEMA3A mutated KS patients and specifically the absence of associated neurological or non neurological clinical disorders will be discussed.