Allelic and genetic heterogeneity of two common genetic diseases

Allelic heterogeneity describes single genes where different alleles can cause different phenotypes. Genetic heterogeneity occurs where two diseases caused by mutations in different genes have similar phenotypes. Two diseases form the basis for this dissertation: thanatophoric dysplasia (TD) and spinal muscular atrophy (SMA).; The fibroblast growth factor receptor 3 (FGFR3) gene was sequenced in prenatal dwarfism patients ascertained by ultrasound. Heterozygous FGFR3 mutations cause a spectrum of dwarfing syndromes, including TD types I and II. Analyzed patients did not have the most common TD associated mutations, so the FGFR3 gene was sequenced to determine if allelic heterogeneity accounted for abnormal phenotypes. Two patients had previously described mutations; no new mutations were found. Additional allelic heterogeneity of FGFR3 does not appear to account for disease phenotypes in these patients.; Survival of Motor Neuron (SMN) 1 and 2 copy number were analyzed on SMA carrier tests. Homozygous deletion or mutation of at least exon 7 of SMN1 is linked to approximately 95% of spinal muscular atrophy (SMA) patients. Increased copy number of SMN2 is linked to milder disease. Three clinically asymptomatic individuals, with no SMN1 and five copies of SMN2, and various family members, are described. These families further support the role of SMN2 in modifying the SMA disease phenotype.; The coding region of immunoglobulin mu binding protein 2 (IGHMBP2) was sequenced in patients with no mutations or deletions of SMN1 but a phenotype suggesting SMA. IGHMBP2 is implicated in SMA with respiratory distress (SMARD), which has striking phenotypic similarities to SMA. Eleven previously undescribed base changes are reported. These mutations do not account for disease status in a significant number of patients. In this population, SMARD has no significant genetic heterogeneity with SMA.; The Smn gene of five hundred forty-two zebrafish was examined for deletions and single base mutations as the first step in producing an SMA model. Zebrafish neuromuscular development is well characterized and relatively simple; also, zebrafish Smn is similar to human SMN1. In animal models, it is desirable to mimic human disease closely, making it important to establish zebrafish with specifically mutated Smn to breed disease expressing fish.