Journal Article

<i>SEMA3A</i> deletion in a family with Kallmann syndrome validates the role of semaphorin 3A in human puberty and olfactory system development

Jacques Young, Corinne Metay, Jerome Bouligand, Bassim Tou, Bruno Francou, Luigi Maione, Lucie Tosca, Julie Sarfati, Frédéric Brioude, Blandine Esteva, Audrey Briand-Suleau, Sophie Brisset, Michel Goossens, Gerard Tachdjian and Anne Guiochon-Mantel

in Human Reproduction

Published on behalf of European Society of Human Reproduction and Embryology

Volume 27, issue 5, pages 1460-1465
Published in print May 2012 | ISSN: 0268-1161
Published online March 2012 | e-ISSN: 1460-2350 | DOI: http://dx.doi.org/10.1093/humrep/des022
SEMA3A deletion in a family with Kallmann syndrome validates the role of semaphorin 3A in human puberty and olfactory system development

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BACKGROUND

Kallmann syndrome (KS) is a genetic disorder associating pubertal failure with congenitally 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% of cases of KS. Here, we attempted to identify new genes responsible for KS by using a pan-genomic approach.

METHODS

From a cohort of 120 KS patients, we selected 48 propositi with no mutations in known KS genes. They were analyzed by comparative genomic hybridization array, using Agilent 105K oligonucleotide chips with a mean resolution of 50 kb.

RESULTS

One propositus was found to have a heterozygous deletion of 213 kb at locus 7q21.11, confirmed by real-time qPCR, deleting 11 of the 17 SEMA3A exons. This deletion cosegregated in the propositus' family with the KS phenotype, that was transmitted in autosomal dominant fashion and was not associated with other neurological or non-neurological clinical disorders. SEMA3A codes for semaphorin 3A, a protein that interacts with neuropilins. Mice lacking semaphorin 3A expression have been showed to have a Kallmann-like phenotype.

CONCLUSIONS

SEMA3A is therefore a new gene whose loss-of-function is involved in KS. These findings validate the specific role of semaphorin 3A in the development of the olfactory system and in neuronal control of puberty in humans.

Keywords: puberty; Kallmann; hypogonadotropic hypogonadism; GnRH; neuropilin; semaphorin 3A

Journal Article.  3685 words.  Illustrated.

Subjects: Reproductive Medicine

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