| Description |
To improve the understanding of limb development and congenital limb defects, I have studied five disorders: ulnar-mammary syndrome (UMS), camptodactyly with hearing loss (CAHL), distal arthrogryposis type 1 (DA1), distal arthrogryposis type 2 (DA2) and distal arthrogryposis type 2B (DAM). The purpose of each study was to attempt to identify the gene, which when mutated, causes the given disorder. The experimental approach included clinical description, linkage analysis and gene cloning. Families affected with the various disorders, were ascertained and described clinically; as a result of the careful clinical analysis, the distal arthrogryposes have been reclassified to include eleven disorders, and a new form of distal arthrogryposis has been identified (DAM). Additionally, clinical information and DNA has been collected from over 70 DA2 individuals. Four linkage studies resulted in chromosomal localization of three genes: DA1 (9p21-q13), UMS (12q23-24.1) and DA2B (11p15.5-tel); the CAHL gene has been excluded from over 230 loci. Gene cloning resulted in the identification of TBX3 as the gene responsible for UMS and the exclusion of a candidate gene, TNNT3, as a cause of DA2B. The main immediate benefit of gene identification for affected individuals has been a more accurate diagnosis, using either haplotype or mutation analysis (DA1 or UMS patients). Eventually, treatments, such as gene therapy, should become available. Finally, each congenital limb malformation gene discovery and characterization provides us with a better understanding of limb development. Coexpression. of mutant and normal minK demonstrated that mutations suppress IKs channel function. KVLQT1, HERG, SCN5A and minK encode ion channel subunits involved in the generation of the cardiac action potential. Mutations can lead to channel dysfunction and delayed myocellular repolarization. The aberrant cardiac repolarization creates a substrate for arrhythmia. KVLQT1 and minK are also expressed in the inner ear. We demonstrated that homozygous mutations in KVLQT1 can cause deafness and the severe cardiac phenotype associated with Jervell and Lange-Nielsen syndrome. Loss of functional channels in the ear disrupts the production of endolymph, leading to deafness. Finally, we defined the complete genomic structure of KVLQT1, HERG and minK and designed primers for the amplification of each exon. This information was used to identify 138 new LQT-associated mutations. This enables presymptomatic diagnosis of LQT in the affected families and has implications for the prevention and treatment of this life-threatening disorder. |
