SHH – Holoprosencephaly

SHH encodes a secreted morphogen essential for ventral forebrain patterning. Heterozygous loss-of-function variants in SHH cause autosomal dominant holoprosencephaly (HPE), a spectrum ranging from alobar defects to microforms such as solitary median maxillary central incisor (SMMCI). Variation in penetrance and expressivity is well documented, with both familial and sporadic cases.

Genetic studies have identified SHH mutations in over 740 unrelated individuals with HPE, including 344 probands in a cohort screening of 344 cases (PMID:10556296) and 396 cases in a separate series (PMID:22791840). Variants span missense, nonsense, frameshift, splice, and microdeletion classes. Segregation analysis in families, including six affected relatives across two generations, supports autosomal dominant inheritance with variable expressivity (PMID:11919111). A recurrent mutation hotspot at codon 100 and founder alleles have been reported.

Functional assays demonstrate that many SHH missense and nonsense mutations impair autocatalytic processing, ligand-receptor binding, and downstream signaling. Five of seven N-terminal domain variants (e.g., p.Gln100His, p.Trp117Arg) show reduced Ptc-binding and signaling potency in cell-based reporters (PMID:16282375). Additional studies reveal that certain variants act as dominant negatives, further reducing SHH activity (PMID:15292211).

Animal models confirm that Shh haploinsufficiency recapitulates HPE phenotypes. In vivo patterning assays show that mutant SHH fails to induce ventral neuronal markers and midline structures in the developing nervous system (PMID:12709790). Mouse knock-out and transgenic rescue experiments underscore a dosage-sensitive requirement for SHH in forebrain morphogenesis.

While the preponderance of data affirm SHH as a definitive HPE gene, rare SHH variants of uncertain significance and normal polymorphisms have been reported in controls, underscoring the need for combined genetic and functional evaluation. No large-scale refutations of the SHH–HPE link exist.

Collectively, heterozygous SHH variants are a definitive cause of autosomal dominant HPE, supported by extensive proband and family studies and concordant functional evidence. SHH mutation screening and functional assessment are critical for accurate molecular diagnosis and genetic counseling of HPE.

References

• Annals of Neurology • 2000 • Sonic hedgehog signal peptide mutation in a patient with holoprosencephaly. PMID:10762164
• Archives of Disease in Childhood • 2002 • Extreme variability of expression of a Sonic Hedgehog mutation: attention difficulties and holoprosencephaly. PMID:11919111
• Human Molecular Genetics • 1999 • The mutational spectrum of the sonic hedgehog gene in holoprosencephaly: SHH mutations cause a significant proportion of autosomal dominant holoprosencephaly. PMID:10556296
• Journal of Medical Genetics • 2012 • Genotypic and phenotypic analysis of 396 individuals with mutations in Sonic Hedgehog. PMID:22791840
• Proceedings of the National Academy of Sciences of the United States of America • 2005 • Molecular mechanisms of Sonic hedgehog mutant effects in holoprosencephaly. PMID:16282375
• Human Genetics • 2004 • Functional characterization of sonic hedgehog mutations associated with holoprosencephaly. PMID:15292211
• Human Genetics • 2003 • SONIC HEDGEHOG mutations causing human holoprosencephaly impair neural patterning activity. PMID:12709790

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