Feather, Sally Anne; (1999) The molecular genetics of human renal tract malformations. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

This thesis describes work in two contrasting renal tract malformations: the oral-facial-digital syndrome type 1 (OFD1) and primary vesicoureteric reflux (VUR). I mapped OFD1 to an 18cM interval on the short arm of the X chromosome between the telomeric marker DXS996 and the centromeric marker DXS7105, using samples from two pedigrees with five affected females with OFD1, with a lod score of 3.32 at an intragenic polymorphic marker at KAL. Microsatellite marker analysis of three additional pedigrees with OFD1 did not narrow the region further. I examined the expression of candidate genes KAL, APXL, FXY and calbindin in human fetal tissue using reverse transcription. I performed mutation screening by SSCP on the candidate genes KAL, APXL, CLC4, FXY, ARHGAP6, GRPR, SCML1, RAIR2 and STK9 and excluded them as candidates for OFD1. I performed histological studies on renal tissue from an affected female with OFD1 to characterise the origin of the renal cysts as glomerulocystic in the polycystic renal disease in OFD1. I performed a collaborative genome wide scan in seven pedigrees with VUR and reflux nephropathy (RN) and analysed the results using GENEHUNTER parametric and non-parametric linkage (NPL) analysis. The analysis was performed separately for analysis V (individuals with VUR only), analysis R ( individuals with RN only) and analysis T (individuals with either VUR or RN). The results revealed a major locus on chromosome one between the markers D1S1613 and D1S1653 with a maximum NPL score of 5.48 and a p value of 0.0002. The results suggested genetic heterogeneity with additional loci on chromosomes 3, 8 and 20. The candidate regions chromosomes 6p and 10q did not reach significance in this analysis but a region on the X chromosome reached significance with a NPL score of 0.58 and a p value of 0.04.

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