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@ARTICLE{Oleari:166386,
author = {R. Oleari and V. Andrè and A. Lettieri and S. Tahir and L.
Roth and A. Paganoni and I. Eberini and C. Parravicini and
V. Scagliotti and L. Cotellessa and F. Bedogni and L. B. De
Martini and M. V. Corridori and S. Gulli and H. G.
Augustin$^*$ and C. Gaston-Massuet and K. Hussain and A.
Cariboni},
title = {{A} novel {SEMA}3{G} mutation in two siblings affected by
syndromic {G}n{RH} deficiency.},
journal = {Neuroendocrinology},
volume = {111},
number = {5},
issn = {1423-0194},
address = {Basel},
publisher = {Karger},
reportid = {DKFZ-2020-02874},
pages = {421-441},
year = {2021},
note = {2021;111(5):421-441},
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.},
cin = {A190},
ddc = {610},
cid = {I:(DE-He78)A190-20160331},
pnm = {311 - Zellbiologie und Tumorbiologie (POF4-311)},
pid = {G:(DE-HGF)POF4-311},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:32365351},
doi = {10.1159/000508375},
url = {https://inrepo02.dkfz.de/record/166386},
}