ABHD5 – Dorfman-Chanarin Disease

ABHD5 (formerly CGI-58) is the causative gene for Dorfman-Chanarin disease (DCD; MONDO:0010155), a rare autosomal recessive lipid storage disorder characterized by congenital non-bullous ichthyosiform erythroderma, systemic triglyceride accumulation, and multisystem involvement including hepatic steatosis and cirrhosis. The gene was first linked to DCD in 2001 when eight distinct ABHD5 mutations (nonsense, frameshift, splice-site, missense) were identified in 13 patients from nine families of Mediterranean descent, defining the NCIE2 locus and establishing the gene–disease relationship (PMID:11590543).

Inheritance follows an autosomal recessive pattern, with homozygous or compound heterozygous ABHD5 variants leading to defective lipase/esterase co-activation and accumulation of neutral lipids in multiple tissues, manifesting as ichthyosis, hepatomegaly, myopathy, hearing loss, and variable neurologic involvement. Over 160 affected individuals across >40 unrelated families harbor pathogenic ABHD5 alleles, including recurrent founder and private loss-of-function variants (e.g., c.700C>T (p.Arg234Ter)) (PMID:11590543, PMID:33455044).

Segregation data demonstrate clear co-segregation of biallelic ABHD5 variants with DCD in consanguineous and multiplex pedigrees, with at least 19 additional affected relatives showing concordant genotypes and phenotypes. Case series report homozygous nonsense mutations (e.g., R184X) and splice-site changes leading to truncated protein lacking the α/β hydrolase fold and catalytic triad, correlating with severe ichthyosis and early cirrhosis (PMID:14708602, PMID:15127008).

Functional assays provide strong experimental evidence: CGI-58 is an essential activator of adipose triglyceride lipase (ATGL), enhancing TG hydrolase activity up to 20-fold. CDS-associated ABHD5 point mutants fail to bind or activate ATGL in vitro, while wild-type ABHD5 expression in patient fibroblasts restores lipolysis and reverses TG accumulation (PMID:16679289). Additional cell-based and lipidomic studies reveal that ABHD5 mutations impair ω-O-acylceramide production by PNPLA1, linking ABHD5 loss to barrier defects underlying ichthyosis (PMID:30527376).

No studies have reported convincing conflicting evidence; all identified loss-of-function variants in ABHD5 consistently co-segregate with DCD. Animal and cellular models recapitulate key histopathologic features including lipid vacuoles in lamellar granules and hepatosteatosis, reinforcing mechanistic insights.

In summary, ABHD5 exhibits a definitive gene–disease relationship with Dorfman-Chanarin disease based on decades of genetic and functional concordance. Early recognition by skin findings and peripheral blood smear (Jordan’s anomaly) enables prompt molecular confirmation. Key take-home: ABHD5 genetic testing is essential for diagnosis, family counseling, and targeted management in DCD.

References

• American Journal of Human Genetics | 2001 | Mutations in CGI-58, the gene encoding a new protein of the esterase/lipase/thioesterase subfamily, in Chanarin-Dorfman syndrome PMID:11590543
• Journal of Investigative Dermatology | 2003 | Truncation of CGI-58 protein causes malformation of lamellar granules resulting in ichthyosis in Dorfman-Chanarin syndrome PMID:14708602
• Cell Metabolism | 2006 | Adipose triglyceride lipase-mediated lipolysis of cellular fat stores is activated by CGI-58 and defective in Chanarin-Dorfman Syndrome PMID:16679289
• Journal of Dermatological Science | 2018 | Molecular mechanism of the ichthyosis pathology of Chanarin-Dorfman syndrome: Stimulation of PNPLA1-catalyzed ω-O-acylceramide production by ABHD5 PMID:30527376
• Liver International | 2021 | Chanarin-Dorfman Syndrome: A comprehensive review PMID:33455044

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