DDB2 – Xeroderma Pigmentosum Group E

Xeroderma pigmentosum (XP) is a rare autosomal recessive photodermatosis characterized by extreme ultraviolet sensitivity and a high predisposition to skin cancers. XP complementation group E (XP-E) results from biallelic mutations in DDB2, which encodes the UV-damaged DNA-binding protein essential for global genome nucleotide excision repair. Loss of DDB2 disrupts early lesion recognition, leading to defective removal of cyclobutane pyrimidine dimers and 6-4 photoproducts and consequent skin carcinogenesis.

Genetic evidence includes at least 10 unrelated probands with homozygous or compound heterozygous truncating and missense alleles in DDB2 (PMID:32530099; PMID:32228487; PMID:10469312), with segregation in three additional affected siblings from consanguineous families (PMID:32530099). Variants span the coding sequence and include recurrent stop-gain changes and small indels, exemplified by c.1063C>T (p.Arg355Ter), all consistent with autosomal recessive inheritance and loss of function.

Functional assays in XP-E patient cells show complete loss of UV-damaged DNA binding activity and deficiency in post-replication repair of 6-4 photoproducts (PMID:12812979), while in vitro ubiquitylation assays demonstrate that wild-type DDB2 is directly modified by the Cullin 4A ubiquitin ligase complex, a process abrogated by disease-causing variants (PMID:15811626). Overexpression of DDB2 enhances removal of UV lesions and confers resistance to UV-induced apoptosis in cell models, confirming its protective role.

The concordant genetic and biochemical data provide definitive evidence that DDB2 deficiency causes XP-E. Clinical sequencing of DDB2 enables precise diagnosis, informs photoprotection strategies, and guides genetic counseling for affected families.

Key take-home: DDB2 mutation analysis is critical for definitive XP-E diagnosis and personalized UV-protection management.

References

• International journal of dermatology • 2020 • Novel mutation identified in the DDB2 gene in patients with xeroderma pigmentosum group-E. PMID:32530099
• BMC medical genetics • 2020 • Identification of a novel DDB2 mutation in a Chinese Han family with Xeroderma pigmentosum group E: a case report and literature review. PMID:32228487
• The Journal of investigative dermatology • 1999 • A newly identified patient with clinical xeroderma pigmentosum phenotype has a non-sense mutation in the DDB2 gene and incomplete repair in (6-4) photoproducts. PMID:10469312
• Human molecular genetics • 2003 • True XP group E patients have a defective UV-damaged DNA binding protein complex and mutations in DDB2 which reveal the functional domains of its p48 product. PMID:12812979
• DNA repair • 2005 • DDB2, the xeroderma pigmentosum group E gene product, is directly ubiquitylated by Cullin 4A-based ubiquitin ligase complex. PMID:15811626
• Journal of dermatological science • 2018 • Whole Exome Sequencing allows the identification of two novel groups of Xeroderma pigmentosum in Tunisia, XP-D and XP-E: Impact on molecular diagnosis. PMID:29169765

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