A Novel Homozygous <b><i>WDR72</i></b> Mutation in Two Siblings with Amelogenesis Imperfecta and Mild Short Stature

Abstract

Amelogenesis imperfecta (AI) is a clinically and genetically heterogeneous group of inherited defects of enamel formation. In isolated AI (no additional segregating features), mutations in at least 7 genes are known so far, causing dominant, recessive or X-linked AI and allowing the identification of the molecular etiology in 40–50% of affected families. We report on 2 siblings (an 11-year-old female and a 7-year-old male) born to consanguineous Turkish parents, with AI and mild, proportionate short stature. Both parents have normal teeth, but mother, maternal grandmother and great-grandfather are/were also of short stature. A spine X-ray performed in the girl excluded brachyolmia. Affymetrix GenomeWide SNP6.0 Array analysis identified no pathogenic copy number changes, but showed sharing of large homozygous regions, including chromosome band 15q21.3 containing the WDR72 gene. WDR72 sequence analysis in both siblings revealed homozygosity for a novel stop mutation in exon 10 (c.997A>T, p.Lys333X) explaining the AI phenotype. Mutations in WDR72 are a very rare cause of autosomal-recessive hypomaturation type of isolated AI. The mutation described in our patients specifies the diagnosis AI IIA3 and represents only the sixth WDR72 mutation reported so far. The WDR72 protein is critical for dental enamel formation, but its exact function is still unknown.

Distal renal tubular acidosis caused by tryptophan‐aspartate repeat domain 72 (WDR72) mutations

“…Mutations in WDR72 have previously been identified as the cause of AI (OMIM*613214), which includes a diverse group of hereditary diseases that affect tooth enamel formation . To date, 10 different AI‐causing mutations in WDR72 have been reported, and all showed a recessive pattern of inheritance of hypomaturation AI . By a genome‐wide association study, WDR72 was also associated with kidney function and chronic kidney diseases, and single‐nucleotide polymorphisms on WDR72 were also found to be associated with the glomerulus filtration rate variance in American Indians .…”

“…25 To date, 10 different AI-causing mutations in WDR72 have been reported, and all showed a recessive pattern of inheritance of hypomaturation AI. [24][25][26][27][28][29][30][31] By a genome-wide association study, WDR72 was also associated with kidney function and chronic kidney diseases, 32 and single-nucleotide polymorphisms on WDR72 were also found to be associated with the glomerulus filtration rate variance in American Indians. 33 The Wdr72 knockout mice showed defective dental enamel formation without the appearance of other organ abnormalities.…”

Critical roles for WDR72 in calcium transport and matrix protein removal during enamel maturation

“…Since mutations in WDR72 (15q21.3) were first identified to cause autosomal recessive hypomaturation AI, there have been seven different disease-causing mutations identified in 10 families (El-Sayed et al 2009Lee et al 2010;Wright et al 2011;Kuechler et al 2012;Katsura et al 2014). All of the mutations are located sporadically throughout the gene (exons 8, 10, 12, 15, 16, and 17) and truncate the protein (either nonsense or frameshift mutations) if translated.…”

“…2011; Kuechler et al. 2012; Katsura et al. 2014), the functions of WDR72 and its role in enamel maturation remain largely unknown.…”

“…The discovery that mutations in WDR72 (WD repeat-containing protein 72; OMIM *613214) cause autosomal recessive hypomaturation AI, first demonstrated that this gene is critical for enamel maturation (El-Sayed et al 2009). While seven different disease-causing WDR72 mutations have been identified to date (El-Sayed et al 2009Lee et al 2010;Wright et al 2011;Kuechler et al 2012;Katsura et al 2014), the functions of WDR72 and its role in enamel maturation remain largely unknown. Human WDR72 encodes an intracellular protein of 1102 amino acids with no known functional domains except a b-propeller structure composed of WD40 repeat domains in its N-terminus.…”