title: PEX6 is Expressed in Photoreceptor Cilia and Mutated in Deafblindness with Enamel Dysplasia and Microcephaly.
abstract: Deafblindness is part of several genetic disorders. We investigated a consanguineous Egyptian family with two siblings affected by congenital hearing loss and retinal degeneration, initially diagnosed as Usher syndrome type 1. At teenage, severe enamel dysplasia, developmental delay, and microcephaly became apparent. Genome-wide homozygosity mapping and whole-exome sequencing detected a homozygous missense mutation, c.1238G>T (p.Gly413Val), affecting a highly conserved residue of peroxisomal biogenesis factor 6, PEX6. Biochemical profiling of the siblings revealed abnormal and borderline plasma phytanic acid concentration, and cerebral imaging revealed white matter disease in both. We show that Pex6 localizes to the apical extensions of secretory ameloblasts and differentiated odontoblasts at early stages of dentin synthesis in mice, and to cilia of retinal photoreceptor cells. We propose PEX6, and possibly other peroxisomal genes, as candidate for the rare cooccurrence of deafblindness and enamel dysplasia. Our study for the first time links peroxisome biogenesis disorders to retinal ciliopathies.
authors.affiliation: Department of Clinical Genetics, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt.
authors.forename: Maha S
authors.initials: MS
authors.lastname: Zaki
authors.affiliation: Institute of Human Genetics, University Hospital of Cologne, Cologne, Germany.
authors.forename: Raoul
authors.initials: R
authors.lastname: Heller
authors.affiliation: Institute of Human Genetics, University Hospital of Cologne, Cologne, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Thoenes
authors.affiliation: Cologne Center for Genomics (CCG) and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
authors.forename: Gudrun
authors.initials: G
authors.lastname: Nürnberg
authors.affiliation: Department of Cell and Matrix Biology, Institute of Zoology, Johannes Gutenberg University of Mainz, Mainz, Germany.
authors.forename: Gabi
authors.initials: G
authors.lastname: Stern-Schneider
authors.affiliation: Cologne Center for Genomics (CCG) and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.|Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.affiliation: Institute for Anatomy and Cell Biology, Justus Liebig University, Giessen, Germany.
authors.forename: Srikanth
authors.initials: S
authors.lastname: Karnati
authors.affiliation: Computational Biology Group, Oxford Gene Technology, Oxford, United Kingdom.
authors.forename: Daniel
authors.initials: D
authors.lastname: Swan
authors.affiliation: Department of Biochemical Genetics, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt.
authors.forename: Ekram
authors.initials: E
authors.lastname: Fateen
authors.affiliation: Department of Cell and Matrix Biology, Institute of Zoology, Johannes Gutenberg University of Mainz, Mainz, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Nagel-Wolfrum
authors.affiliation: Department of Orodental Genetics, Orodental Research Division, National Research Centre, Cairo, Egypt.
authors.forename: Mostafa I
authors.initials: MI
authors.lastname: Mostafa
authors.affiliation: Cologne Center for Genomics (CCG) and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Thiele
authors.affiliation: Department of Cell and Matrix Biology, Institute of Zoology, Johannes Gutenberg University of Mainz, Mainz, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Wolfrum
authors.affiliation: Institute for Anatomy and Cell Biology, Justus Liebig University, Giessen, Germany.
authors.forename: Eveline
authors.initials: E
authors.lastname: Baumgart-Vogt
authors.affiliation: Institute of Human Genetics, University Hospital of Cologne, Cologne, Germany.|Bioscientia Center for Human Genetics, Ingelheim, Germany.
authors.forename: Hanno J
authors.initials: HJ
authors.lastname: Bolz
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D000251:Adenosine Triphosphatases / Q000235:genetics* / Q000378:metabolism; D000565:Ameloblasts / Q000378:metabolism / Q000473:pathology; D000595:Amino Acid Sequence; D000818:Animals; D002648:Child; D002923:Cilia / Q000378:metabolism / Q000473:pathology; D003241:Consanguinity; D054062:Deaf-Blind Disorders / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D003744:Dental Enamel Hypoplasia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D015870:Gene Expression; D006720:Homozygote; D006801:Humans; D008297:Male; D051379:Mice; D008831:Microcephaly / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009804:Odontoblasts / Q000378:metabolism / Q000473:pathology; D010375:Pedigree; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism / Q000473:pathology; D012162:Retinal Degeneration / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D035781:Siblings; D066127:White Matter / Q000378:metabolism / Q000473:pathology; D055815:Young Adult
chemical_list: D000251:Adenosine Triphosphatases; D000074183:ATPases Associated with Diverse Cellular Activities; C490759:PEX6 protein, human
keywords: PEX6; deafblindness; enamel dysplasia; peroxisome biogenesis disorders; retinal ciliopathy