title: Heimler Syndrome Is Caused by Hypomorphic Mutations in the Peroxisome-Biogenesis Genes PEX1 and PEX6.
abstract: Heimler syndrome (HS) is a rare recessive disorder characterized by sensorineural hearing loss (SNHL), amelogenesis imperfecta, nail abnormalities, and occasional or late-onset retinal pigmentation. We ascertained eight families affected by HS and, by using a whole-exome sequencing approach, identified biallelic mutations in PEX1 or PEX6 in six of them. Loss-of-function mutations in both genes are known causes of a spectrum of autosomal-recessive peroxisome-biogenesis disorders (PBDs), including Zellweger syndrome. PBDs are characterized by leukodystrophy, hypotonia, SNHL, retinopathy, and skeletal, craniofacial, and liver abnormalities. We demonstrate that each HS-affected family has at least one hypomorphic allele that results in extremely mild peroxisomal dysfunction. Although individuals with HS share some subtle clinical features found in PBDs, the diagnosis was not suggested by routine blood and skin fibroblast analyses used to detect PBDs. In conclusion, our findings define HS as a mild PBD, expanding the pleiotropy of mutations in PEX1 and PEX6.
authors.affiliation: Centre de Génomique Humaine, Faculté de Médecine et de Pharmacie, Université Mohammed V, 10100 Rabat, Morocco.
authors.forename: Ilham
authors.initials: I
authors.lastname: Ratbi
authors.affiliation: Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, Amsterdam 1105 AZ, the Netherlands.
authors.forename: Kim D
authors.initials: KD
authors.lastname: Falkenberg
authors.affiliation: Department of Medical Genetics, University of Antwerp, Antwerp 2610, Belgium.
authors.forename: Manou
authors.initials: M
authors.lastname: Sommen
authors.affiliation: Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester Academic Health Sciences Centre, Manchester M13 9WL, UK; Manchester Centre for Genomic Medicine, Institute of Human Development, University of Manchester, Manchester M13 9WL, UK.
authors.forename: Nada
authors.initials: N
authors.lastname: Al-Sheqaih
authors.affiliation: Centre de Génomique Humaine, Faculté de Médecine et de Pharmacie, Université Mohammed V, 10100 Rabat, Morocco.
authors.forename: Soukaina
authors.initials: S
authors.lastname: Guaoua
authors.affiliation: Department of Medical Genetics, University of Antwerp, Antwerp 2610, Belgium.
authors.forename: Geert
authors.initials: G
authors.lastname: Vandeweyer
authors.affiliation: Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester Academic Health Sciences Centre, Manchester M13 9WL, UK; Manchester Centre for Genomic Medicine, Institute of Human Development, University of Manchester, Manchester M13 9WL, UK.
authors.forename: Jill E
authors.initials: JE
authors.lastname: Urquhart
authors.affiliation: Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester Academic Health Sciences Centre, Manchester M13 9WL, UK; Manchester Centre for Genomic Medicine, Institute of Human Development, University of Manchester, Manchester M13 9WL, UK.
authors.forename: Kate E
authors.initials: KE
authors.lastname: Chandler
authors.affiliation: Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester Academic Health Sciences Centre, Manchester M13 9WL, UK; Manchester Centre for Genomic Medicine, Institute of Human Development, University of Manchester, Manchester M13 9WL, UK.
authors.forename: Simon G
authors.initials: SG
authors.lastname: Williams
authors.affiliation: Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester Academic Health Sciences Centre, Manchester M13 9WL, UK; Manchester Centre for Genomic Medicine, Institute of Human Development, University of Manchester, Manchester M13 9WL, UK.
authors.forename: Neil A
authors.initials: NA
authors.lastname: Roberts
authors.affiliation: Département de Pédodontie-Prévention, Faculté de Médecine Dentaire, Université Mohammed V, BP 6212 Madinat Al Irfane, 10100 Rabat, Morocco; Service d'Odontologie, Hôpital Militaire d'Instruction Mohamed V, Avenue des Far, Hay Riad, 10100 Rabat, Morocco.
authors.forename: Mustapha
authors.initials: M
authors.lastname: El Alloussi
authors.affiliation: Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester Academic Health Sciences Centre, Manchester M13 9WL, UK; Manchester Centre for Genomic Medicine, Institute of Human Development, University of Manchester, Manchester M13 9WL, UK.
authors.forename: Graeme C
authors.initials: GC
authors.lastname: Black
authors.affiliation: Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, Amsterdam 1105 AZ, the Netherlands.
authors.forename: Sacha
authors.initials: S
authors.lastname: Ferdinandusse
authors.affiliation: Département de Pédodontie-Prévention, Faculté de Médecine Dentaire, Université Mohammed V, BP 6212 Madinat Al Irfane, 10100 Rabat, Morocco.
authors.forename: Hind
authors.initials: H
authors.lastname: Ramdi
authors.affiliation: Division of Human Genetics, Schneider Children's Hospital of Long Island Jewish Medical Center, New Hyde Park, NY 11042, USA.
authors.forename: Audrey
authors.initials: A
authors.lastname: Heimler
authors.affiliation: Department of Clinical Genetics, Liverpool Women's NHS Foundation Trust, Liverpool L8 7SS, UK.
authors.forename: Alan
authors.initials: A
authors.lastname: Fryer
authors.affiliation: National Centre for Medical Genetics, Our Lady's Children's Hospital, Crumlin, Dublin 12, Ireland; Department of Genetics, Children's University Hospital, Dublin 12, Ireland.
authors.forename: Sally-Ann
authors.initials: SA
authors.lastname: Lynch
authors.affiliation: West Midlands Regional Genetics Service, Birmingham Women's Hospital NHS Trust, Birmingham B15 2TG, UK.
authors.forename: Nicola
authors.initials: N
authors.lastname: Cooper
authors.affiliation: West Midlands Regional Genetics Service, Birmingham Women's Hospital NHS Trust, Birmingham B15 2TG, UK.
authors.forename: Kai Ren
authors.initials: KR
authors.lastname: Ong
authors.affiliation: Leeds Institute of Biomedical and Clinical Sciences, St. James's University Hospital, University of Leeds, Leeds LS9 7TF, UK.
authors.forename: Claire E L
authors.initials: CE
authors.lastname: Smith
authors.affiliation: Leeds Institute of Biomedical and Clinical Sciences, St. James's University Hospital, University of Leeds, Leeds LS9 7TF, UK.
authors.forename: Christopher F
authors.initials: CF
authors.lastname: Inglehearn
authors.affiliation: Leeds Institute of Biomedical and Clinical Sciences, St. James's University Hospital, University of Leeds, Leeds LS9 7TF, UK; School of Dentistry, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Mighell
authors.affiliation: Academic Unit of Oral Health and Development, School of Clinical Dentistry, University of Sheffield, S10 2TA, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Elcock
authors.affiliation: Leeds Institute of Biomedical and Clinical Sciences, St. James's University Hospital, University of Leeds, Leeds LS9 7TF, UK.
authors.forename: James A
authors.initials: JA
authors.lastname: Poulter
authors.affiliation: Department of Medical Genetics and National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge, Cambridge CB2 0QQ, UK; Department of Clinical Genetics, East Anglian Regional Genetics Service, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
authors.forename: Marc
authors.initials: M
authors.lastname: Tischkowitz
authors.affiliation: Institute of Medical Genetics, University Hospital of Wales, Cardiff CF14 4XW, UK.
authors.forename: Sally J
authors.initials: SJ
authors.lastname: Davies
authors.affiliation: Centre de Génomique Humaine, Faculté de Médecine et de Pharmacie, Université Mohammed V, 10100 Rabat, Morocco; Département de Génétique Médicale, Institut National d'Hygiène, BP 769 Agdal, 10090 Rabat, Morocco.
authors.forename: Abdelaziz
authors.initials: A
authors.lastname: Sefiani
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester M13 9PL, UK.
authors.forename: Aleksandr A
authors.initials: AA
authors.lastname: Mironov
authors.affiliation: Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester Academic Health Sciences Centre, Manchester M13 9WL, UK; Manchester Centre for Genomic Medicine, Institute of Human Development, University of Manchester, Manchester M13 9WL, UK.
authors.forename: William G
authors.initials: WG
authors.lastname: Newman
authors.affiliation: Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, Amsterdam 1105 AZ, the Netherlands. Electronic address: h.r.waterham@amc.uva.nl.
authors.forename: Hans R
authors.initials: HR
authors.lastname: Waterham
authors.affiliation: Department of Medical Genetics, University of Antwerp, Antwerp 2610, Belgium. Electronic address: guy.vancamp@uantwerpen.be.
authors.forename: Guy
authors.initials: G
authors.lastname: Van Camp
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D000251:Adenosine Triphosphatases / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000567:Amelogenesis Imperfecta / Q000235:genetics*; D016022:Case-Control Studies; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D005500:Follow-Up Studies; D006319:Hearing Loss, Sensorineural / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D009264:Nails, Malformed / Q000235:genetics*; D010375:Pedigree; D020675:Peroxisomes / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D011379:Prognosis; D015996:Survival Rate; D055815:Young Adult
chemical_list: D008565:Membrane Proteins; D000251:Adenosine Triphosphatases; D000074183:ATPases Associated with Diverse Cellular Activities; C111808:PEX1 protein, human; C490759:PEX6 protein, human