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Mutations in the human Sonic Hedgehog gene cause holoprosencephaly
E Roessler1, E Belloni, K Gaudenz
1Children's Hospital of Philadelphia, Division of Human Genetics and Molecular Biology, Pennsylvania, USA.
Nature Genetics
|November 1, 1996
Summary
Holoprosencephaly (HPE), a severe brain and facial defect, is linked to mutations in the Sonic Hedgehog (SHH) gene. This discovery identifies the first gene responsible for HPE, advancing understanding of this developmental disorder.
Area of Science:
- Developmental Biology
- Human Genetics
- Medical Research
Background:
- Holoprosencephaly (HPE) is a common congenital defect affecting forebrain and midface development.
- HPE presents a wide spectrum of clinical severity, from mild anomalies to severe forms incompatible with life.
- The genetic and molecular basis of HPE remains largely unknown, despite identified environmental and chromosomal factors.
Purpose of the Study:
- To identify the specific gene responsible for Holoprosencephaly type 3 (HPE3).
- To investigate the molecular etiology of autosomal dominant HPE (ADHPE).
Main Methods:
- Analysis of 30 families with autosomal dominant HPE.
- Genetic sequencing to identify mutations in candidate genes, specifically focusing on the HPE3 locus on chromosome 7q36.
- Segregation analysis of identified mutations within affected families.
Main Results:
- The human Sonic Hedgehog (SHH) gene was identified as the HPE3 gene.
- Five out of 30 ADHPE families showed segregation of distinct heterozygous SHH mutations.
- Identified mutations included premature termination codons and alterations in conserved residues critical for SHH protein function.
Conclusions:
- Sonic Hedgehog (SHH) is the first identified gene causing Holoprosencephaly.
- SHH mutations are a significant cause of autosomal dominant HPE.
- These findings provide crucial insights into the molecular mechanisms underlying HPE and its associated phenotypes.