Journal Article

DKFZ-2020-02874

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png A novel SEMA3G mutation in two siblings affected by syndromic GnRH deficiency.

Oleari, R. ; Andrè, V. ; Lettieri, A. ; Tahir, S. ; Roth, L. ; Paganoni, A. ; Eberini, I. ; Parravicini, C. ; Scagliotti, V. ; Cotellessa, L. ; Bedogni, F. ; De Martini, L. B. ; Corridori, M. V. ; Gulli, S. ; Augustin, H. G.DKFZ* ; Gaston-Massuet, C. ; Hussain, K. ; Cariboni, A.

2021
Karger Basel

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Please use a persistent id in citations: doi:10.1159/000508375

Abstract: Gonadotropin-releasing hormone (GnRH) deficiency causes hypogonadotropic hypogonadism (HH), a rare genetic disorder that impairs sexual reproduction. HH can be due to defective GnRH-secreting neuron development or function and may be associated with other clinical signs in overlapping genetic syndromes. With most of the cases being idiopathic, genetics underlying HH is still largely unknown.To assess the contribution of mutated Semaphorin 3G (SEMA3G) gene in the onset of a syndromic form of HH, characterized by intellectual disabilities and facial dysmorphic features.By combining homozygosity mapping with exome sequencing, we identified a novel variant in SEMA3G gene. We then applied mouse as a model organism to examine SEMA3G expression and its functional requirement in vivo. Further, we applied homology modelling in silico and cell culture assays in vitro to validate the pathogenicity of the identified gene variant.We found that: SEMA3G is expressed along the migratory route of GnRH neurons and in the developing pituitary; SEMA3G affects GnRH neuron development, but is redundant in the adult hypothalamic-pituitary-gonadal axis; mutated SEMA3G alters binding properties in silico and in vitro to its PlexinAs receptors and attenuates its effect on the migration of immortalized GnRH neurons.In silico, in vitro and in vivo models revealed that SEMA3G regulates GnRH neuron migration and that its mutation affecting receptor selectivity may be responsible for the HH-related defects.

Note: 2021;111(5):421-441

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Contributing Institute(s):

1. A190 Vaskuläre Onkologie und Metastasierung (A190)

Research Program(s):

1. 311 - Zellbiologie und Tumorbiologie (POF4-311) (POF4-311)

Appears in the scientific report 2021

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