The Mutational Spectrum of the Sonic Hedgehog Gene in Holoprosencephaly: SHH Mutations Cause a Significant Proportion of Autosomal Dominant Holoprosencephaly

Abstract

Holoprosencephaly (HPE) is a common developmental anomaly of the human forebrain and midface where the cerebral hemispheres fail to separate into distinct left and right halves. We have previously reported haploinsufficiency for Sonic Hedgehog ( SHH ) as a cause for HPE. We have now performed mutational analysis of the complete coding region and intron-exon junctions of the SHH gene in 344 unrelated affected individuals. Herein, we describe 13 additional unrelated affected individuals with SHH mutations, including nonsense and missense mutations, deletions and an insertion. These mutations occur throughout the extent of the gene. No specific genotype-phenotype association is evident based on the correlation of the type or position of the mutations. In conjunction with our previous studies, we have identified a total of 23 mutations in 344 unrelated cases of HPE. They account for 14 cases of familial HPE and nine cases of sporadic HPE. Mutations in SHH were detected in 10 of 27 (37%) families showing autosomal dominant transmission of the HPE spectrum, based on structural anomalies. Interestingly, three of the patients with an SHH mutation also had abnormalities in another gene that is expressed during forebrain development. We suggest that the interactions of multiple gene products and/or environmental elements may determine the final phenotypic outcome for a given individual and that variations among these factors may cause the wide variability in the clinical features seen in HPE.

Molecular mechanisms of Sonic hedgehog mutant effects in holoprosencephaly

“…The three of these five that clearly cosegregate with an HPE phenotype (G31R, W117G, and W117R) showed the strongest functional impairments (see below). A fourth, D88V, although not associated with HPE in the heterozygous mother of the proband, shows a pattern of cosegregation in second-degree relatives that could be consistent with incomplete penetrance of the mutation (19). The fifth alteration, N115K, is not associated with HPE in the mother of the proband, and no other evidence of cosegregation with phenotype exists.…”

A new mutation in the six-domain of SIX3 gene causes holoprosencephaly

“…Furthermore, such ophthalmologic signs have been described, associated with SHH mutations. 11 The variable expression of the SIX3 mutations might be explained by environmental factors and/or potential modifying genes. This hypothesis was supported by Nanni et al 11 who reported three patients with both an SHH mutation and abnormalities in ZIC2 or TGIF genes.…”

A practical guide to the management of anophthalmia and microphthalmia

“…20,[22][23][24][25][26] Several syndromic genes are involved in developing other organs in addition to the eye, including CHD7, the gene for CHARGE syndrome 27,28 and PTCH, the gene for Gorlin syndrome. 29 There is a complex interplay between the different eye development gene pathways, which allows their expression to be finely regulated 5,27,30 and begins to explain why there is such an overlap of the phenotypes associated with mutations of each gene. For a more complete list of conditions associated with coloboma, the reader is referred to the reviews by Gregory-Evans et al and Chang et al 5,6 …”