NEW YORK (GenomeWeb) – A study published online today in the American Journal of Human Genetics suggests that a rare condition called Heimler syndrome stems from mutations that turn down the activity of proteins produced from two genes previously linked to peroxisome biogenesis disorders.
An international team led by investigators in Amsterdam, Belgium, and the UK did exome sequencing on members of eight families affected by Heimler syndrome, a condition characterized by sensineural hearing loss, fingernail and eye abnormalities.
In six of the eight families, the researchers uncovered mutations affecting both copies of either the PEX1 or PEX6 gene — alterations expected to produce partial loss of function for the genes. Because complete loss-of-function mutations in the same genes have been linked to a more severe set of conditions called peroxisome biogenesis disorders, they speculated that Heimler syndrome might represent a less pronounced form of peroxisome disorder.
"Although individuals with [Heimler syndrome] share some subtle clinical features found in [peroxisome biogenesis disorders], the diagnosis was not suggested by routine blood and skin fibroblast analyses used to detect [peroxisome biogenesis disorders]," co-corresponding authors Guy Van Camp, a medical genetics researcher at the University of Antwerp, and genetic metabolic diseases researcher Hans Waterham at the University of Amsterdam, and their colleagues wrote.
Based on such patterns, they argued that "our findings define [Heimler syndrome] as a mild [peroxisome biogenesis disorder], expanding the pleiotropy of mutations in PEX1 and PEX6."
Although Heimler syndrome was first described more than two decades ago, there is still much debate about its underlying cause, the team noted, with some arguing that it may be due to mutations affecting ectodermal tissue development, and others pointing to Heimler syndrome features that overlap with those found in ciliopathies.
For their new analysis, Waterham, Camp, and colleagues started by sequencing affected individuals from seven of the eight families included in the study, using Illumina HiSeq 1500 or 2500 instruments to sequence protein-coding portions of the genome captured from blood or saliva samples with Illumina Nextera Rapid Capture or Agilent SureSelect kits.
The team saw biallelic mutations in PEX1 in four of these families, while an affected individual from a fifth family carried mutations affecting both copies of PEX6. The latter gene was also altered in affected individuals from a family tested by targeted Sanger sequencing on PEX1 and PEX6.
The same mutations were rare or missing from the publicly available or in-house databases that the researchers scrutinized, suggesting they may be involved in Heimler syndrome pathogenesis.
In unaffected members of the families, meanwhile, they found that the PEX1 or PEX6 mutations were either missing or affected only one copy of the gene in question.
The team's follow-up efforts to characterize peroxisomal phenotypes in fibroblast cells from individuals with Heimler syndrome suggest the PEX1 or PEX6 mutations present in affected individuals diminished but didn't completely wipe out peroxisome biogenesis.
Such findings hint that even a modest improvement in peroxisomal function might improve symptoms for those suffering from more severe peroxisome biogenesis disorders, the researchers noted.
"Our combined findings show that [Heimler syndrome] is caused by compound heterozygosity for a loss-of-function allele and a hypomorphic allele in PEX1 or PEX6," they wrote. "Consequently … [Heimler syndrome] represents a discrete phenotypic entity at the mildest end of the [peroxisome biogenesis disorder] clinical spectrum."