POFUT1 – Dowling-Degos disease

Dowling-Degos disease (DDD) is a rare autosomal dominant genodermatosis characterized by reticular hyperpigmentation of flexural areas such as the neck, axillae, and groin [HP:0007588]. POFUT1 encodes protein O-fucosyltransferase 1, an enzyme critical for O-fucosylation of epidermal growth factor-like repeats in Notch receptors, with a conserved role in melanocyte differentiation and epidermal patterning.

In a large Chinese pedigree with generalized DDD, genome-wide linkage mapped the disease locus to chromosome 20 and exome sequencing identified a heterozygous nonsense mutation c.430G>T (p.Glu144Ter) in POFUT1 that co-segregated with disease (n=9 affected) ([PMID:23684010]). An additional unrelated DDD individual harbored a heterozygous frameshift deletion c.482delA (p.Lys161SerfsTer42) in POFUT1 ([PMID:23684010]).

A phenotypic expansion was reported in a 9-year-old female with mosaic POFUT1 loss: paired exome sequencing revealed a germline frameshift and somatic copy-neutral loss of heterozygosity encompassing POFUT1, associated with segmental hyper- and hypopigmented patches with eczematous lesions ([PMID:31566882]).

Inheritance is autosomal dominant, with pathogenic variants acting via haploinsufficiency. POFUT1-negative DDD alleles are distinct from KRT5 and POGLUT1 mutations, underscoring locus heterogeneity in DDD.

Functional assays showed that POFUT1 knockdown in HaCaT keratinocytes reduced NOTCH1, NOTCH2, HES1, and KRT5 expression. Morpholino knockdown of zebrafish pofut1 produced hypopigmentation and abnormal melanin distribution by 72 hpf, with tyrosinase activity decreased by 45%, recapitulating human DDD features ([PMID:23684010]).

Collectively, heterozygous loss-of-function variants in POFUT1 cause DDD through impaired Notch signaling in the skin. Clinical sequencing of POFUT1 informs diagnosis and genetic counseling, and Notch pathway modulation may offer therapeutic potential.

References

• American journal of human genetics • 2013 • Mutations in POFUT1, encoding protein O-fucosyltransferase 1, cause generalized Dowling-Degos disease. PMID:23684010
• American journal of medical genetics. Part A • 2019 • Phenotypic expansion of POFUT1 loss of function mutations in a disorder featuring segmental dyspigmentation with eczematous and folliculo-centric lesions. PMID:31566882

Evidence Based Scoring (AI generated)