ABCB6 – Dyschromatosis Universalis Hereditaria

ABCB6 variants underlie dyschromatosis universalis hereditaria (DUH), an autosomal dominant pigmentary genodermatosis characterized by mixed hyperpigmented and hypopigmented macules distributed over the body. Initial linkage and exome sequencing in a Chinese pedigree identified ABCB6 as the causative gene, with subsequent studies confirming its role in multiple families and sporadic cases.

ABCB6 mutations, including c.1663C>A (p.Gln555Lys) co-segregating in 21 affected individuals (PMID:24224009), and additional missense variants c.1067T>C (p.Leu356Pro), c.508A>G (p.Ser170Gly), and c.1736G>A (p.Gly579Glu) in a five-generation family and sporadic patients (PMID:23519333), have been reported. Further exome analysis in a multiplex family uncovered c.1358C>T (p.Ala453Val) and c.964A>C (p.Ser322Lys) in four additional families and two sporadic cases (PMID:24498303).

These ABCB6 variants exhibit perfect cosegregation with DUH across at least six unrelated families, encompassing over 30 affected relatives (PMID:24224009, PMID:23519333, PMID:24498303).

Functional assays demonstrate that disease-associated ABCB6 mutants mislocalize to the Golgi apparatus instead of endosomal compartments in melanocytes (PMID:23519333). Zebrafish knockdown of abcb6 recapitulates pigmentary defects that are rescued by wild-type but not mutant ABCB6 mRNA, confirming loss-of-function pathogenicity (PMID:24498303). Immunohistochemistry reveals epidermal ABCB6 expression concordant with human skin phenotype (PMID:23519333).

No conflicting studies have been reported, and experimental data align with autosomal dominant haploinsufficiency as the mechanism of pathogenesis. Collectively, ABCB6 is definitively associated with DUH, supporting its use in genetic diagnosis and carrier screening.

Key take-home: ABCB6 genetic testing enables precise diagnosis of autosomal dominant dyschromatosis universalis hereditaria.

References

• PLoS One • 2013 • Novel mutations of ABCB6 associated with autosomal dominant dyschromatosis universalis hereditaria. PMID:24224009
• Journal of Investigative Dermatology • 2013 • Mutations in ABCB6 cause dyschromatosis universalis hereditaria. PMID:23519333
• PLoS One • 2014 • Genome-wide linkage, exome sequencing and functional analyses identify ABCB6 as the pathogenic gene of dyschromatosis universalis hereditaria. PMID:24498303

Evidence Based Scoring (AI generated)