Novel<i>FGF8</i>Mutations Associated with Recessive Holoprosencephaly, Craniofacial Defects, and Hypothalamo-Pituitary Dysfunction

McCabe, Mark J.; Gaston‐Massuet, Carles; Tziaferi, Vaitsa; Gregory, Louise; Alatzoglou, Kyriaki S.; Signore, Massimo; Puelles, Eduardo; Gerrelli, Dianne; Farooqi, I. Sadaf; Raza, Jamal; Walker, Judith S.; Kavanaugh, Scott I.; Tsai, Pei‐San; Pitteloud, Nelly; Martinez-Barbera, Juan Pedro; Dattani, Mehul

doi:10.1210/jc.2011-0454

Cited by 124 publications

(111 citation statements)

References 40 publications

Supporting

Mentioning

104

Contrasting

Unclassified

Order By: Relevance

“…The Fgf signaling pathway has also been suggested to promote ventral telencephalic specification independently of Shh (Gutin et al, 2006). Mutations in FGF8 and FGFR1 have been identified in human patients with HPE (McCabe et al, 2011;Simonis et al, 2013). Fgf signaling is both necessary and sufficient for Foxg1 expression in the ANE (Paek et al, 2009;Shimamura and Rubenstein, 1997).…”

Section: Discussionmentioning

confidence: 99%

Six3 dosage mediates the pathogenesis of holoprosencephaly

et al. 2016

View full text Add to dashboard Cite

Holoprosencephaly (HPE) is defined as the incomplete separation of the two cerebral hemispheres. The pathology of HPE is variable and, based on the severity of the defect, HPE is divided into alobar, semilobar, and lobar. Using a novel hypomorphic Six3 allele, we demonstrate in mice that variability in Six3 dosage results in different HPE phenotypes. Furthermore, we show that whereas the semilobar phenotype results from severe downregulation of Shh expression in the rostral diencephalon ventral midline, the alobar phenotype is caused by downregulation of Foxg1 expression in the anterior neural ectoderm. Consistent with these results, in vivo activation of the Shh signaling pathway rescued the semilobar phenotype but not the alobar phenotype. Our findings show that variations in Six3 dosage result in different forms of HPE.

show abstract

Section: Discussionmentioning

confidence: 99%

Six3 dosage mediates the pathogenesis of holoprosencephaly

et al. 2016

View full text Add to dashboard Cite

show abstract

“…In mouse, Fgf8 expression was observed in the developing Rathke's pouch. Mouse embryos carrying a hypomorphic allele of Fgf8 presented severe abnormalities of the anterior pituitary during development: decreased size, but surprisingly with defects in the terminal differentiation of LH expressing cells only (23). The same team then reported a novel FGF8 heterozygous synonymous change (p.T72T) in a patient with GH, TSH and ACTH deficiency, pubertal delay, and a bulky anterior pituitary; despite the synonymous nature of the change, this variant was predicted to alter splicing and ligand signalling activity (19).…”

Section: European Journal Of Endocrinologymentioning

confidence: 99%

MECHANISMS IN ENDOCRINOLOGY: An update in the genetic aetiologies of combined pituitary hormone deficiency

Castinetti¹,

Reynaud²,

Saveanu³

et al. 2016

European Journal of Endocrinology

View full text Add to dashboard Cite

Over the last 5 years, new actors involved in the pathogenesis of combined pituitary hormone deficiency in humans have been reported: they included a member of the immunoglobulin superfamily glycoprotein and ciliary G protein-coupled receptors, as well as new transcription factors and signalling molecules. New modes of inheritance for alterations of genes encoding transcription factors have also been described. Finally, actors known to be involved in a very specific phenotype (hypogonadotroph hypogonadism for instance) have been identified in a wider range of phenotypes. These data thus suggest that new mechanisms could explain the low rate of aetiological identification in this heterogeneous group of diseases. Taking into account the fact that several reviews have been published in recent years on classical aetiologies of CPHD such as mutations of POU1F1 or PROP1, we focused the present overview on the data published in the last 5 years, to provide the reader with an updated review on this rapidly evolving field of knowledge.

show abstract

“…Recently, mutations in OTX2 and FGF8 genes have been described in patients with SOD. [2][3][4] Interestingly, OTX2 and FGF8…”

Section: Discussionmentioning

confidence: 99%

“…1 However, an increasing number of early developmental transcription factors and associated pathway genes have been implicated in the etiology of SOD, ie, HESX1, SOX2, SOX3, OTX2, PROKR2, FGF1, and FGF8. [2][3][4] These genes are expressed in regions that determine the formation of forebrain and related midline structures, such as the hypothalamus and pituitary gland, and mutations in these genes are therefore associated with marked phenotypic heterogeneity. Classically, the diagnosis of SOD is made when 2 or more features of the classic triad of optic nerve hypoplasia, pituitary hormone abnormalities, and midline brain defects are present.…”

mentioning

confidence: 99%