Spectrum of PEX1 and PEX6 variants in Heimler syndrome.
Heimler syndrome (HS) consists of recessively inherited sensorineural hearing loss, amelogenesis imperfecta (AI) and nail abnormalities, with or without visual defects. Recently HS was shown to result from hypomorphic mutations in PEX1 or PEX6, both previously implicated in Zellweger Syndrome Spectrum Disorders (ZSSD). ZSSD are a group of conditions consisting of craniofacial and neurological abnormalities, sensory defects and multi-organ dysfunction. The finding of HS-causing mutations in PEX1 and PEX6 shows that HS represents the mild end of the ZSSD spectrum, though these conditions were previously thought to be distinct nosological entities. Here, we present six further HS families, five with PEX6 variants and one with PEX1 variants, and show the patterns of Pex1, Pex14 and Pex6 immunoreactivity in the mouse retina. While Ratbi et al. found more HS-causing mutations in PEX1 than in PEX6, as is the case for ZSSD, in this cohort PEX6 variants predominate, suggesting both genes play a significant role in HS. The PEX6 variant c.1802G>A, p.(R601Q), reported previously in compound heterozygous state in one HS and three ZSSD cases, was found in compound heterozygous state in three HS families. Haplotype analysis suggests a common founder variant. All families segregated at least one missense variant, consistent with the hypothesis that HS results from genotypes including milder hypomorphic alleles. The clinical overlap of HS with the more common Usher syndrome and lack of peroxisomal abnormalities on plasma screening suggest that HS may be under-diagnosed. Recognition of AI is key to the accurate diagnosis of HS.
Leeds Institute of Biomedical and Clinical Sciences, St. James's University Hospital, University of Leeds, Leeds, UK.
Claire E L
CE
Smith
Leeds Institute of Biomedical and Clinical Sciences, St. James's University Hospital, University of Leeds, Leeds, UK.
James A
0000-0003-2048-5693
JA
Poulter
Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, USA.|Children's Hospital of the King's Daughters, Norfolk, VA, USA.|Pediatric Ophthalmology and Ocular Genetics, Philadelphia, PA, USA.
Alex V
AV
Levin
Pediatric Ophthalmology and Ocular Genetics, Philadelphia, PA, USA.
Jenina E
JE
Capasso
Department of Clinical Genetics, Northampton General Hospital, NHS Trust, Northampton, UK.
Susan
S
Price
Rappaport Faculty of Medicine, Technion, Haifa, Israel.
Tamar
T
Ben-Yosef
The Genetic Institute and Obstetrics and Gynaecology Department, Meir Medical Center, Kfar Saba, Israel.
Reuven
R
Sharony
Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester Academic Health Sciences Centre, Manchester, UK.|Manchester Centre for Genomic Medicine, Institute of Human Development, University of Manchester, Manchester, UK.
William G
WG
Newman
School of Dentistry, Department of Oral Biology, St. James's University Hospital, University of Leeds, Leeds, UK.
Roger C
RC
Shore
School of Dentistry, Department of Oral Biology, St. James's University Hospital, University of Leeds, Leeds, UK.
Steven J
SJ
Brookes
Leeds Institute of Biomedical and Clinical Sciences, St. James's University Hospital, University of Leeds, Leeds, UK.|Department of Oral Medicine, School of Dentistry, University of Leeds, Leeds, UK.
Alan J
AJ
Mighell
Leeds Institute of Biomedical and Clinical Sciences, St. James's University Hospital, University of Leeds, Leeds, UK.
Chris F
CF
Inglehearn
D000074183:ATPases Associated with Diverse Cellular Activities; D000251:Adenosine Triphosphatases / Q000235:genetics* / Q000378:metabolism; D000567:Amelogenesis Imperfecta / Q000175:diagnosis / Q000235:genetics*; D000818:Animals; D059472:Exome; D016368:Frameshift Mutation; D006319:Hearing Loss, Sensorineural / Q000175:diagnosis / Q000235:genetics*; D006579:Heterozygote; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D020125:Mutation, Missense; D009264:Nails, Malformed / Q000175:diagnosis / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D012160:Retina / Q000378:metabolism
D008565:Membrane Proteins; D000251:Adenosine Triphosphatases; D000074183:ATPases Associated with Diverse Cellular Activities; C111808:PEX1 protein, human; C490759:PEX6 protein, human