A heterozygous endothelin 3 mutation in Waardenburg-Hirschsprung disease: is there a dosage effect of EDN3/EDNRB gene mutations on neurocristopathy phenotypes?

SOX10 mutations in chronic intestinal pseudo-obstruction suggest a complex physiopathological mechanism

“…The cysteine newly generated is located in a region, between the mature endothelin sequence and the endothelin-like (ET-like) peptide, which is normally devoid of cysteine, suggesting that the introduction of this new amino acid may alter disulphide bond formation in the endothelin and/or the ET-like peptide regions. Although this hypothesis has to be confirmed, it is consistent with the previously reported role of endothelin and ET-like peptide disulphide bonds in the secondary structure of the preproendothelin that allow enzymatic processing of an inactive protein into a mature active peptide, and with the characterisation of other EDN3 mutations involving cysteines (Fabbrini et al 1993;Hofstra et al 1996Hofstra et al , 1997Pingault et al 2001). The mutation segregates at the heterozygous state in the mother's and in the father's families.…”

Review and update of mutations causing Waardenburg syndrome

“…Following the subsequent observations of heterozygous mutations of EDNRB (and to a lesser extent, of EDN3) in isolated HD and homozygous mutations in WS4, it was suggested that WS4 was inherited as a recessive condition and HD as a dominant condition with incomplete penetrance. Since then, however, several cases of dominant transmission with incomplete penetrance have been described in WS4, associated with EDN3 or EDNRB mutations [Pingault et al, 2001[Pingault et al, , 2002Syrris et al, 1999] and this article). Extensive review of the published mutations and our new observations reveal the following points.…”

Genetic and phenotypic heterogeneity in two novel cases of Waardenburg syndrome type IV

“…Autosomal recessive forms are caused by mutations in the homozygous state in EDN3 or EDNRB [Puffenberger et al, 1994;Atti e et al, 1995;Edery et al, 1996;Hofstra et al, 1996;Bidaud et al, 1997;Boardman et al, 2001;Verheij et al, 2002;Sangkhathat et al, 2005], but some heterozygous carriers show part of the clinical features of the syndrome. Autosomal dominant forms are caused by mutations in the heterozygous state in EDN3, EDNRB, or SOX10 [Pingault et al, 1998[Pingault et al, , 2001[Pingault et al, , 2002Southard-Smith et al, 1999;Syrris et al, 1999;Sham et al, 2001;Mor ın et al, 2008]. Mutations affecting SOX10 result in a great phenotypic variability, including not only the canonical WS4, but ranging from the more severe PCWH phenotype (Peripheral demyelinating neuropathy, Central dysmyelinating leukodystrophy, and Waardenburg-Hirschsprung features, OMIM 609136) [Inoue et al, 1999[Inoue et al, , 2002[Inoue et al, , 2004Pingault et al, 2000;Touraine et al, 2000;Verheij et al, 2006] to milder forms with only pigmentary abnormalities and sensorineural hearing impairment, but no Hirschsprung disease [Bondurand et al, 1999[Bondurand et al, , 2007Iso et al, 2008].…”