Individuals with autosomal recessive congenital ichthyoses (ARCIs) have scaling and flaky skin due to skin barrier defects. Identifying genetic causes of ARCIs is difficult owing to the rarity and heterogeneity of these diseases. Based on the observation that a skin condition with similar features occurs spontaneously in golden retrievers, Grall et al. carried out a genome-wide association study (GWAS) of 40 dogs and identified a causative mutation in PNPLA1, a previously uncharacterised protein. They subsequently identified PNPLA1 mutations in two unrelated families with ARCI not yet linked with other mutations, and found similar abnormalities in skin biopsies from patients and affected dogs. Further studies of PNPLA1 showed that it is present in the upper epidermis and suggest that it functions in epidermal glycerophospholipid metabolism; disease-associated mutations seem to alter the levels of lipids that are important for cell membrane integrity. These data provide new information about the pathological mechanisms underlying at least one form of ARCI and, more broadly, about skin barrier formation. Furthermore, they suggest that studies of ichthyoses common to different dog breeds might shed light on other genes involved in human ARCIs.
Clues to human ichthyosis from GWAS of golden retrievers
Clues to human ichthyosis from GWAS of golden retrievers. Dis Model Mech 1 March 2012; 5 (2): 149. doi:
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