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Am J Hum Genet. 2015 Oct 1;97(4):535-45. doi: 10.1016/j.ajhg.2015.08.011. Epub 2015 Sep 17.

Heimler Syndrome Is Caused by Hypomorphic Mutations in the Peroxisome-Biogenesis Genes PEX1 and PEX6.

Author information

1
Centre de Génomique Humaine, Faculté de Médecine et de Pharmacie, Université Mohammed V, 10100 Rabat, Morocco.
2
Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, Amsterdam 1105 AZ, the Netherlands.
3
Department of Medical Genetics, University of Antwerp, Antwerp 2610, Belgium.
4
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.
5
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.
6
Département de Pédodontie-Prévention, Faculté de Médecine Dentaire, Université Mohammed V, BP 6212 Madinat Al Irfane, 10100 Rabat, Morocco.
7
Division of Human Genetics, Schneider Children's Hospital of Long Island Jewish Medical Center, New Hyde Park, NY 11042, USA.
8
Department of Clinical Genetics, Liverpool Women's NHS Foundation Trust, Liverpool L8 7SS, UK.
9
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.
10
West Midlands Regional Genetics Service, Birmingham Women's Hospital NHS Trust, Birmingham B15 2TG, UK.
11
Leeds Institute of Biomedical and Clinical Sciences, St. James's University Hospital, University of Leeds, Leeds LS9 7TF, UK.
12
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.
13
Academic Unit of Oral Health and Development, School of Clinical Dentistry, University of Sheffield, S10 2TA, UK.
14
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.
15
Institute of Medical Genetics, University Hospital of Wales, Cardiff CF14 4XW, UK.
16
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.
17
Faculty of Life Sciences, University of Manchester, Manchester M13 9PL, UK.
18
Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, Amsterdam 1105 AZ, the Netherlands. Electronic address: h.r.waterham@amc.uva.nl.
19
Department of Medical Genetics, University of Antwerp, Antwerp 2610, Belgium. Electronic address: guy.vancamp@uantwerpen.be.

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.

PMID:
26387595
PMCID:
PMC4596894
DOI:
10.1016/j.ajhg.2015.08.011
[Indexed for MEDLINE]
Free PMC Article

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