Evaluation of heritable human phenotypes when coupled with molecular genetic approaches can yield insights about the genes involved in fundamental biological processes.
Brachydactyly
Underdevelopment of hands and feet.
Can result from pleiotropic syndromes.
(see definition below)
Isolated brachydactylies are frequently heritable, highly penetrant, and variably expressive. Subtypes based on characteristic pattern of skeletal development.
Collected genomic DNA from members of families with disorder.
Every family member’s chromosomes 1 to 22 tested for linkage to the BDC locus with highly polymorphic genetic markers spaced 25 cM apart.
Using PCR rxns, evidence of linkage was found on chromosome 20.
Additional markers were tested in the vicinity and a 15 cM interval was identified.
BDC locus was assigned to a 15 cM interval on chromosome 20q.
How do you find the responsible gene?
Functional cloning – know all about the product of the gene. Can use this to figure out its genome.
Positional cloning – know its inheritance pattern. Use mapping.
15 cM interval contains 300 genes!!
In order to narrow this down the team looked around until they found out that mice with a mutation in the same region have a disorder called brachypodism (small feet).
As it turned out someone else had already cloned the gene in humans and called it = CDMP1.
The team sequenced the gene in one affected and one unaffected family members. They found a nonsense mutation in the middle of the CDMP1 coding sequence!