PEX6 mutation causing deafblindness with enamel dysplasia and microcephaly

Abstract

Purpose: Deafblindness is part of many genetic syndromes, with Usher syndrome predominanting. We aimed at identifying the genetic basis for congenital profound hearing loss and retinitis pigmentosa, initially diagnosed as Usher syndrome type 1 (USH1), in two siblings of a consanguineous Egyptian family. Both patients have dysmorphic facial features, amelogenesis imperfecta, microcephaly and mental retardation.

Methods: We conducted whole-exome sequencing of one patient’s sample. Homozygosity-by-descent regions identified by genomewide linkage analysis were used for additional filtering of WES data. Confirmation and segregation analysis of variants of interest were carried out by conventional Sanger sequencing. Plasma phytanic acid concentration was determined in EDTA blood samples from both patients. We chose tooth tissue of P2 day old mice to label PEX6 protein abundance in ameloblasts and odontoblasts by exposure to polyclonal rabbit antiserum against PEX6.

Results: We detected a previously undescribed homozygous missense mutation, c.1238G>T (p.Gly413Val), in PEX6, encoding a cytoplasmic AAA-ATPase involved in peroxisomal biogenesis. The mutation affects an evolutionarily highly conserved residue and was not present in large-scale sequencing databases or in dbSNP. It cosegregated with the phenotype in the family, and the clinical diagnosis was reversed to peroxisome biogenesis disorder (PBD). In line with causality of this mutation, biochemical profiling revealed elevated plasma phytanic acid concentration in one patient and values in the upper normal range in the other. In P2 mice, PEX6 localized to the apical extensions of the secretory ameloblasts (polarization progress and differentiation process) and of the differentiated odontoblasts (at the beginning of the dentin synthesis).

Conclusions: Our findings indicate a crucial role of PEX6 not only for retinal and cochlear integrity, but also for tooth development. Enamel dysplasia has not yet been described in genetically confirmed cases of PBD. However, there have been reports on families diagnosed as „atypical“ USH and Refsum syndrome with enamel dysplasia. We propose PEX6, and possibly other peroxisomal genes, as candidate for these rare syndromic retinopathies. Importantly, a diet low in phytanic acid would represent a potential therapy approach in these cases.