Novel FGF8 mutations associated with recessive holoprosencephaly, craniofacial defects, and hypothalamo-pituitary dysfunction.

Détails

ID Serval
serval:BIB_E54363578798
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Novel FGF8 mutations associated with recessive holoprosencephaly, craniofacial defects, and hypothalamo-pituitary dysfunction.
Périodique
Journal of Clinical Endocrinology and Metabolism
Auteur(s)
McCabe M.J., Gaston-Massuet C., Tziaferi V., Gregory L.C., Alatzoglou K.S., Signore M., Puelles E., Gerrelli D., Farooqi I.S., Raza J., Walker J., Kavanaugh S.I., Tsai P.S., Pitteloud N., Martinez-Barbera J.P., Dattani M.T.
ISSN
1945-7197 (Electronic)
ISSN-L
0021-972X
Statut éditorial
Publié
Date de publication
2011
Volume
96
Numéro
10
Pages
E1709-E1718
Langue
anglais
Résumé
Context: Fibroblast growth factor (FGF) 8 is important for GnRH neuronal development with human mutations resulting in Kallmann syndrome. Murine data suggest a role for Fgf8 in hypothalamo-pituitary development; however, its role in the etiology of wider hypothalamo-pituitary dysfunction in humans is unknown.Objective: The objective of this study was to screen for FGF8 mutations in patients with septo-optic dysplasia (n = 374) or holoprosencephaly (HPE)/midline clefts (n = 47).Methods: FGF8 was analyzed by PCR and direct sequencing. Ethnically matched controls were then screened for mutated alleles (n = 480-686). Localization of Fgf8/FGF8 expression was analyzed by in situ hybridization in developing murine and human embryos. Finally, Fgf8 hypomorphic mice (Fgf8(loxPNeo/-)) were analyzed for the presence of forebrain and hypothalamo-pituitary defects.Results: A homozygous p.R189H mutation was identified in a female patient of consanguineous parentage with semilobar HPE, diabetes insipidus, and TSH and ACTH insufficiency. Second, a heterozygous p.Q216E mutation was identified in a female patient with an absent corpus callosum, hypoplastic optic nerves, and Moebius syndrome. FGF8 was expressed in the ventral diencephalon and anterior commissural plate but not in Rathke's pouch, strongly suggesting early onset hypothalamic and corpus callosal defects in these patients. This was consolidated by significantly reduced vasopressin and oxytocin staining neurons in the hypothalamus of Fgf8 hypomorphic mice compared with controls along with variable hypothalamo-pituitary defects and HPE.Conclusion: We implicate FGF8 in the etiology of recessive HPE and potentially septo-optic dysplasia/Moebius syndrome for the first time to our knowledge. Furthermore, FGF8 is important for the development of the ventral diencephalon, hypothalamus, and pituitary. (J Clin Endocrinol Metab 96: E1709-E1718, 2011)
Pubmed
Web of science
Open Access
Oui
Création de la notice
10/11/2011 9:59
Dernière modification de la notice
20/08/2019 16:08
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