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Hypomaturation amelogenesis imperfecta due to WDR72 mutations: a novel mutation and ultrastructural analyses of deciduous teeth.

ABSTRACT: Mutations in WDR72 have been identified in autosomal recessive hypomaturation amelogenesis imperfecta (AI).to describe a novel WDR72 mutation and report the ultrastructural enamel phenotype associated with a different WDR72 mutation.A family segregating autosomal recessive hypomaturation AI was recruited, genomic DNA obtained and WDR72 sequenced. Four deciduous teeth from one individual with a previously published WDR72 mutation, extracted as part of clinical care, were subjected to scanning electron microscopy, energy-dispersive X-ray analysis and transverse microradiography.A novel homozygous nonsense mutation, R897X, was identified in WDR72 in a family originating from Pakistan. Ultrastructural analysis of enamel from the deciduous teeth of an AI patient with the WDR72 mutation S783X revealed energy-dispersive X-ray analysis spectra with normal carbon and nitrogen peaks, excluding retention of enamel matrix protein. However, transverse microradiography values were significantly lower for affected teeth when compared to normal teeth, consistent with reduced mineralisation. On scanning electron microscopy the enamel rod form observed was normal, yet with inter-rod enamel more prominent than in controls. This appearance was unaltered following incubation with either ?-chymotrypsin or lipase.The novel WDR72 mutation described brings the total reported WDR72 mutations to four. Analyses of deciduous tooth enamel in an individual with a homozygous WDR72 mutation identified changes consistent with a late failure of enamel maturation without retention of matrix proteins. The mechanisms by which intracellular WDR72 influences enamel maturation remain unknown.

SUBMITTER: El-Sayed W

PROVIDER: S-EPMC3128158 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Hypomaturation amelogenesis imperfecta due to WDR72 mutations: a novel mutation and ultrastructural analyses of deciduous teeth.

El-Sayed W W Shore R C RC Parry D A DA Inglehearn C F CF Mighell A J AJ

Cells, tissues, organs 20101229 1

<h4>Background</h4>Mutations in WDR72 have been identified in autosomal recessive hypomaturation amelogenesis imperfecta (AI).<h4>Objective</h4>to describe a novel WDR72 mutation and report the ultrastructural enamel phenotype associated with a different WDR72 mutation.<h4>Methods</h4>A family segregating autosomal recessive hypomaturation AI was recruited, genomic DNA obtained and WDR72 sequenced. Four deciduous teeth from one individual with a previously published WDR72 mutation, extracted as ...[more]

PMID: 21196691

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Project description:Amelogenesis Imperfecta (AI) represents a group of hereditary conditions that manifest tooth enamel defects. Several causative mutations in the WDR72 gene have been identified and patients with WDR72 mutations have brown (or orange-brown) discolored enamel, rough enamel surface, early loss of enamel after tooth eruption, and severe attrition. Although the molecular function of WDR72 is not yet fully understood, a recent study suggested that WDR72 could be a facilitator of endocytic vesicle trafficking, which appears inconsistent with the previously reported cytoplasmic localization of WDR72. Therefore, the aims of our study were to investigate the tissues and cell lines in which WDR72 was expressed and to further determine the sub-cellular localization of WDR72. The expression of Wdr72 gene was investigated in mouse tissues and cell lines. Endogenous WDR72 protein was detected in the membranous fraction of ameloblast cell lines in addition to the cytosolic fraction. Sub-cellular localization studies supported our fractionation data, showing WDR72 at the Golgi apparatus, and to a lesser extent, in the cytoplasmic area. In contrast, a WDR72 AI mutant form that lacks its C-terminal region was exclusively detected in the cytoplasm. In addition, our studies identified a putative prenylation/CAAX motif within the last four amino acids of human WDR72 and generated a WDR72 variant, called CS mutant, in which the putative motif was ablated by a point mutation. Interestingly, mutation of the putative CAAX motif impaired WDR72 recruitment to the Golgi. Cell fractionation assays confirmed subcellular distribution of wild-type WDR72 in both cytosolic and membranous fractions, while the WDR72 AI mutant and CS mutant forms were predominantly detected in the cytosolic fraction. Our studies provide new insights into the subcellular localization of WDR72 and demonstrate a critical role for the C-terminal CAAX motif in regulating WDR72 recruitment to the Golgi. In accordance with structural modelling studies that classified WDR72 as a potential vesicle transport protein, our findings suggest a role for WDR72 in vesicular Golgi transport that may be key to understanding the underlying cause of AI.

Dataset Information

Hypomaturation amelogenesis imperfecta due to WDR72 mutations: a novel mutation and ultrastructural analyses of deciduous teeth.

Publications

Hypomaturation amelogenesis imperfecta due to WDR72 mutations: a novel mutation and ultrastructural analyses of deciduous teeth.

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