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A chromosome 21 critical region does not cause specific Down syndrome phenotypes
L E Olson1, J T Richtsmeier, J Leszl
1Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Science (New York, N.Y.)
|October 23, 2004
Summary
The Down syndrome critical region (DSCR) on chromosome 21 does not solely cause craniofacial changes in Down syndrome. Specific DSCR genes are neither sufficient nor necessary for the facial phenotype observed in Down syndrome.
Area of Science:
- Genetics
- Developmental Biology
- Human Disease Modeling
Background:
- Down syndrome (DS) is a genetic disorder associated with trisomy of chromosome 21.
- Craniofacial dysmorphology is a hallmark feature of Down syndrome.
- The "Down syndrome critical region" (DSCR) on chromosome 21 has been hypothesized to harbor genes responsible for DS-related features.
Purpose of the Study:
- To investigate the necessity and sufficiency of the DSCR genes in causing craniofacial dysmorphology characteristic of Down syndrome.
- To test the prevailing hypothesis regarding gene action within the DSCR in the context of Down syndrome phenotypes.
Main Methods:
- Utilized chromosome engineering in mice to create models with specific trisomy or monosomy for the mouse ortholog of the DSCR.
- Assessed craniofacial skeletal dysmorphologies in these engineered mice.
- Compared phenotypes with mice exhibiting larger segmental trisomies relevant to Down syndrome.
Main Results:
- Mice engineered to be trisomic or monosomic solely for the DSCR segment did not exhibit the expected craniofacial dysmorphies.
- The genes within the DSCR were found to be neither sufficient nor largely necessary for producing the facial phenotype associated with Down syndrome.
- Observed craniofacial phenotypes in mice with larger segmental trisomies showed parallels with Down syndrome.
Conclusions:
- The prevailing hypothesis that specific genes within the DSCR are solely responsible for Down syndrome-related craniofacial dysmorphology is refuted.
- The genetic basis of craniofacial features in Down syndrome is more complex than previously assumed, involving genes outside the DSCR or complex interactions.
- Mouse models with precise chromosomal alterations are valuable tools for dissecting the genetic underpinnings of complex genetic disorders like Down syndrome.
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