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CASE STUDY|One foot or another
In humans the HOXD homeotic gene cluster plays a critical role in limb development. In one large family, 16 of 36 members expressed one of two dominantly inherited malformations of the feet known as rocker bottom foot (CVT) or claw foot (CMT). One individual had one foot with CVT and the other with CMT. Genomic analysis identified a single missense mutation in the HOXD10 gene, resulting in a single amino acid substitution in the homeodomain of the encoded transcription factor. This region is crucial for making contact and binding to the target genes controlled by this protein. All family members with the foot malformations were heterozygotes; all unaffected members were homozygous for the normal allele.
Given that affected heterozygotes carry one normal allele of the HOXD10 gene, how might a dominant mutation in a gene encoding a transcription factor lead to a developmental malformation?
Case summary:
In this case16 of 36 members of a large family were found to have one of the two malformations of the feet called claw foot (CMT) or rocker bottom foot (CVT). Even one individual had both the affected foot, one with CVT and the other with CMT.
Characters in the case:
A family with varying foot malformations.
Adequate information:
HOXD homeotic gene cluster in humans is involved in limb development. A single missense mutationhas been recognized in the HOXD10 gene by genomic analysis. As a result, substitution of a single amino acid took place in the homeodomain of the encoded transcription factor. This region is important as it makes contact and binds to the target genes directed by this protein.
To determine:
A dominant mutation in a gene encoding a transcription factor lead to a developmental malformation.
Given information:
The affected heterozygotes carry one normal allele of the HOXD10 gene, while all unaffected members are homozygous and carry normal alleles.
Explanation of Solution
HOX gene cluster has a role in the development of limb and is responsible to give protein products that act as transcription factors. Four clusters of HOXD gene are present: HOXA, HOXC, HOXB, and HOXD. Thus, combination of 2 to 4 HOX genes form particular structures. Therefore, mutations in only one HOX gene do not result into complete transformation.
HOXD10 belongs to a cluster of HOXD genes located on chromosome 2. Mutations in this gene causes congenital vertical talus (rocker bottom foot or claw foot). A missense mutation was observed in HOXD10 gene, in which substitution of a single nucleotide in the dominant allele might result in a codon coding for different amino acid.
Despite of one normal allele, the person get disease as the mutated allele suppresses the expression of normal allele, leading to severe consequences. This results into the failure of the production of required transcription factor, due to which developmental malformation happened.
Therefore, it can be concluded that missense mutation in a gene that encodes for a transcription factorresults into developmental malformation, even if one normal allele is present.
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Chapter 20 Solutions
Essentials of Genetics (9th Edition) - Standalone book
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