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: Ilham Ratbi, Kim D Falkenberg, Manou Sommen, Nada Al-Sheqaih, Soukaina Guaoua, Geert Vandeweyer, Jill E Urquhart, Kate E Chandler, Simon G Williams, Neil A Roberts, Mustapha El Alloussi, Graeme C Black, Sacha Ferdinandusse, Hind Ramdi, Audrey Heimler, Alan Fryer, Sally-Ann Lynch, Nicola Cooper, Kai Ren Ong, Claire E L Smith, Christopher F Inglehearn, Alan J Mighell, Claire Elcock, James A Poulter, Marc Tischkowitz, Sally J Davies, Abdelaziz Sefiani, Aleksandr A Mironov, William G Newman, Hans R Waterham, Guy Van Camp
• Journal: American journal of human genetics (Am J Hum Genet) Vol. 97 Issue 4 Pg. 535-45 (Oct 01 2015) ISSN: 1537-6605 [Electronic] United States
• PMID: 26387595 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Membrane Proteins
• Adenosine Triphosphatases
• ATPases Associated with Diverse Cellular Activities
• PEX1 protein, human
• PEX6 protein, human

Topics

• ATPases Associated with Diverse Cellular Activities
• Adenosine Triphosphatases (genetics)
• Adolescent
• Adult
• Amelogenesis Imperfecta (genetics)
• Case-Control Studies
• Cells, Cultured
• Child
• Child, Preschool
• Female
• Fibroblasts (metabolism, pathology)
• Follow-Up Studies
• Hearing Loss, Sensorineural (genetics)
• Humans
• Infant
• Infant, Newborn
• Male
• Membrane Proteins (genetics)
• Mutation (genetics)
• Nails, Malformed (genetics)
• Pedigree
• Peroxisomes (metabolism, pathology)
• Phenotype
• Prognosis
• Survival Rate
• Young Adult