NEW YORK (GenomeWeb) – A team of researchers has uncovered mutations in the gene KDSR that appear to contribute to a severe skin condition.
Ichthyoses are a group of severe skin conditions that affect about one in 200,000 people and are marked by dry, scaly, or thickened skin, and KDSR mutations appeared to prevent the skin from sealing in moisture.
As they reported today in the American Journal of Human Genetics, researchers led by Yale University School of Medicine's Lynn Boyden sequenced the exomes of people with ichthyoses to uncover mutations in the KDSR gene. While some affected individuals had mutations in both copies of the gene, two individuals at first only seemed to have one affected gene. But when Boyden and her colleagues looked closer, they found that those two had a KDSR variant not picked up by exome sequencing.
"This underscores the importance of comprehensively investigating unsolved genetic diseases," said Boyden, the first author of the study, in a statement.
The researchers' findings further suggested that a common acne drug could be a potential treatment for these patients,and they reported that it so far has helped the patients who've tried it.
Boyden and her colleagues screened a cohort of 750 people with cornification disorders, including ichthyosis and erythrokeratoderma phenotypes, for known cornification-linked mutations. They then sequenced the exomes of four patients who lacked any known pathogenic mutation.
Through this, the researchers found that each proband in the study had a mutation in the KDSR gene. KDSR encodes 3-ketodihydrosphingosine reductase, an enzyme in the ceramide synthesis pathway.
Two probands were compound heterozygotes for a deleterious and a silent mutation in the KDSR gene, the researchers reported.
However, the researchers suspected that the silent mutation — as the guanine at that site is highly conserved — might alter splicing. Indeed, when they used a splicing assay to examine a skin sample from one patient, they noted an in-frame exonic deletion.
Two other patients, meanwhile, appeared to only carry one KDSR mutation. But by examining aligned reads using the Integrative Genomics Viewer, Boyden and her colleagues noticed that these two patients both had a common, benign KDSR variant that they suspected might mark another KDSR mutation not captured by exome sequencing.
By analyzing a skin sample from one of those probands, the researchers found that exon 9 was missing all detectable KDSR transcripts, even though the patient was heterozygous for the mutation affecting exon 9 skipping. This suggested that the other allele might have an intronic mutation affecting exon 9 splicing or the production of KDSR transcripts in general.
Whole-genome sequencing of that patient uncovered a novel inversion that replaces the KDSR promoter, start codon, and first two exons with an unrelated sequence. This inversion abolishes KDSR expression, the researchers added. PCR analysis found the same inversion in the other proband, they noted.
These KDSR mutations prevent the body from producing ceramides, which are fat molecules that help seal moisture into the skin, the researchers said, adding that ceramides are commonly found in moisturizers and other cosmetics.
According to Boyden and her colleagues, there are three major pathways in complex organisms that produce ceramides, and while KDSR is a key component of one pathway, it's not essential to the others.
As retinoic acid can lead to the stimulation of the other two ceramide-producing pathways, two of the probands in the study have been treated with a systemic retinoic acid derivative — isotreninoin, or Accutane. Such treatment, the researchers reported, appears to have resolved the patients' scale and erythema.