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Marshall syndrome associated with a splicing defect at the COL11A1 locus
A J Griffith1, L K Sprunger, D A Sirko-Osadsa
1Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA. griffith@aya.yale.edu
American Journal of Human Genetics
|June 13, 1998
Summary
Marshall syndrome, a rare skeletal dysplasia, is linked to a COL11A1 gene mutation causing exon skipping. This finding reveals a crucial role for alpha1(XI) collagen in skeletal development and shows allelism with certain Stickler syndrome cases.
Area of Science:
- Genetics
- Molecular Biology
- Developmental Biology
Background:
- Marshall syndrome is a rare autosomal dominant skeletal dysplasia.
- It shares phenotypic similarities with the more common Stickler syndrome.
Purpose of the Study:
- To identify the genetic cause of Marshall syndrome in a large kindred.
- To investigate the role of collagen type XI alpha 1 (COL11A1) in skeletal morphogenesis.
Main Methods:
- Genetic analysis of a large kindred with Marshall syndrome.
- Identification of a splice-donor-site mutation in the COL11A1 gene.
- Analysis of the mutation's effect on the alpha1(XI) collagen polypeptide.
Main Results:
- A G+1-->A splice-donor-site mutation in COL11A1 was identified and cosegregated with the Marshall syndrome phenotype.
- The mutation resulted in in-frame skipping of a 54-bp exon, deleting amino acids 726-743.
- This deletion affects the major triple-helical domain of the alpha1(XI) collagen polypeptide.
Conclusions:
- The alpha1(XI) collagen polypeptide plays a significant role in skeletal morphogenesis beyond cartilage extracellular matrix integrity.
- Marshall syndrome is allelic to Stickler syndrome families with COL11A1 mutations.
- This research clarifies the genetic basis of Marshall syndrome and its relationship to Stickler syndrome.