Use this URL to cite or link to this record in EThOS:
Title: Dissecting the pathway of human tooth development through a genetic survey of human Amelogenesis imperfecta : phenotype/genotype correlations and relevance to biomineralisation
Author: Elsayed, Walid Shaaban Moustafa
ISNI:       0000 0004 2718 9341
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2011
Availability of Full Text:
Access from EThOS:
Amelogenesis imperfecta (AI) is the name given to a clinically and genetically heterogeneous group of enamel biomineralisation defects with Mendelian patterns of inheritance. Enamel quantity and/or quality are affected, with inappropriate retention of enamel matrix proteins in the most cases, resulting in hypoplastic and/or hypomineralised phenotypes. AI most commonly occurs in apparent isolation from other co-segregating clinical abnormalities ('non-syndromic AI'). Instances of AI forming part of a diverse range of syndromes are recognised, but poorly described ('syndromic AI'). To date, reported studies have focused on the X-linked and dominant forms of non-syndromic AI which relate to two enamel matrix proteins (AMELX and ENAM) and more recently a cellular protein of unknown function (FAM83H). Only four mutations in 3 genes (ENAM, KLK4 and MMP20) have been described for autosomal recessive non-syndromic AI. This study aims to gain new insight into the genetic basis and phenotype of autosomal recessively inherited hypomineralised AI, both syndromic and non- syndromic forms, through genetic analysis in consanguineous families. A whole-genome SNP autozygosity screen in a non-syndrmoic AI family of Pakistani origin identified a new locus on chromosome 15q21.3. Sequencing .candidate genes in multiple families revealed four different mutations in the poorly characterised WOR72 gene which resulted in autosomal recessive non-syndromic AI (chapter Ill). Deciduous teeth - VI - extracted as part of clinical care from one individual with homozygous WOR72 mutations, revealed normal enamel rod architecture, yet with abnormal inter-rod enamel revealed by scanning electron microscopy (SEM). Energy-dispersive X- ray (EOX) spectra were characterised by normal carbon (C) and nitrogen (N) peaks, excluding the possibility of retention of enamel matrix protein. However, transverse microradiography (TMR) revealed mineral content values significantly lower when compared to normal teeth, indicating hypomineralisation (chapter Ill). A whole-genome SNP autozygosity screen in a family, with syndromic AI and hypohidrosis identified a second locus on chromosome 11 p15.5- q13.1. Sequencing the exons of every gene within the linked region revealed a missense mutation in the STlM1 gene, which is a calcium ion sensor protein (chapter IV). Analyses of extracted permanent and exfoliated deciduous teeth from the proband patient (VII:3) in family P21 confirmed reduced mineral (as determined by TMR) and increased organic content in enamel (determined by EOX). SEM revealed poor quality enamel prisms which were obscured by an amorphous material. This amorphous material was removed by incubation with a-chymotrypsin, but not by incubation with lipase, which was consistent with the inappropriate presence of protein in the enamel. Western blot analyses of protein extracted from the affected enamel indicated the presence of albumin. The dentine was characterised by abnormal morphology on SEM. The only other clinical abnormality identified was hypohidrosis. In particular, there was no apparent involvement of other ectodermal tissues. 1 } ].
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available