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Molecular genetic studies on disorders of calcium and phosphate homeostasis

Parkinson, David Bryan; (1994) Molecular genetic studies on disorders of calcium and phosphate homeostasis. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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The aim of my project has been to investigate the molecular basis for the mineral disorders of familial hypoparathyroidism and X-linked hypophosphataemic rickets. For familial hypoparathyroidism, autosomal dominant, autosomal recessive and X-linked recessive forms of inheritance have been established. For four pedigrees which show an autosomal mode of inheritance (two recessive and two dominant), I have investigated the parathyroid hormone (PTH) gene on chromosome lip for abnormalities which may be associated with the pathology of the disease. In order to facilitate segregation analysis in these families, I have characterised a novel tetranucleotide polymorphism at the PTH locus. By segregation analysis and direct DNA sequencing of the PTH gene and its associated promoter, I have identified a donor splice site mutation at the exon 2/intron 2 boundary of the PTH gene in one pedigree with autosomal recessive hypoparathyroidism and have demonstrated that this mutation cosegregates with hypoparathyroidism in this family. In order to characterise the effect of this mutation upon PTH mRNA processing, as parathyroid tissue was not available, I have used the sensitivity of the polymerase chain reaction to detect the illegitimate or non-tissue specific transcription of the PTH gene in total RNA isolated from cultured lymphocytes from both unaffected and affected individuals from this family. Analysis of the PTH transcript from affected individuals demonstrated that this mutation caused exon skipping to occur and that the PTH mRNA lacked exon 2 of the coding sequence, thereby causing parathyroid hormone deficiency. Analysis in the other three remaining pedigrees allowed the exclusion of the PTH gene as the cause of hypoparathyroidism. For the X-linked recessive hypoparathyroidism, the gene for which has been localised to the long arm of the X chromosome (Xq26-27), I have used the flanking markers, 4D.8 (locus DXS98) and pCDR1 (locus CDR) from this region for pulsed field gel electrophoresis studies to generate physical map data around this locus. The markers 4D.8 and pCDR1 have been used to screen the ICI yeast artificial chromosome (YAC) library, and I have investigated and characterised the YAC clones obtained from this region containing the gene. In addition, I have investigated the molecular basis of X-linked hypophosphataemic rickets. Using an interspecific backcross segregating for hyp, the putative murine homologue of X-linked hypophosphataemic rickets, I have localised the mouse calbindin D9K gene to the region of the hyp locus and have investigated the possible role of this gene in this disorder of phosphate homeostasis.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Molecular genetic studies on disorders of calcium and phosphate homeostasis
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Biological sciences; Calcium and phosphate homeostasis; Molecular genetic studies
URI: https://discovery.ucl.ac.uk/id/eprint/10106970
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