This study is focused on Utah pedigrees with Alport Syndrome. This study has been active for over 25 years. Dr. Gregory and his coworkers have defined the mode of inheritance of this hereditary nephropathy and have demonstrated clearly that the disorder is X-linked. This conclusion was confirmed by likelihood analysis and subsequently by demonstrating tht disease genes mapped to chromosome X in three families. Additional mutations have been characterized by Dr. Gregory's group and by others. Genetic linkage has been exploited extensively to establish linkage to type 4 collagen genes. An autosomal recessive form of Alport Syndrome was also identified and demonstrated to be linked to the COL4A3/4 locus and in a single family, dominant inheritance was found to be linked to the same locus. The investigators have now completely sequenced the COL4A5 gene and the adjacent untranslated sequences and have designed PCR primers permitting a multiplex PCR mutation screen for defects at this locus. To date, 114 separate mutations have been detected in the investigator's laboratory. There include three large deletions, one small deletion, 19 frame shift mutations, 48 missense mutations, 28 splice site mutations and 15 termination mutations. Missense mutations coding for the non-collagenous domain and adjacent portions of the collagenous domain were generally associated with milder clinical phenotypes than were missense mutations in the 5' half of the gene or with other types of mutations. Sever families with quite mild phenotypes associated with late-onset renal disease and relatively inapparent hearing loss have been associated with mutations of the 3' end of the gene. New pedigrees continue to be recruited for these studies in an effort to define phenotype-genotype correlations, and to identify critical regions of the type 4 collagen genes that effect the structure of the glomerulous and of the structures involved in sensorineural hearing loss.
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