DDB2 – Xeroderma pigmentosum group E

Xeroderma pigmentosum group E (XP-E) is an autosomal recessive disorder characterized by late-onset freckling, photosensitivity and a predisposition to skin cancers in sun-exposed areas. Patients often present in adulthood with hyperpigmented macules and may develop basal cell carcinoma or melanoma without early neurological involvement. XP-E results from biallelic loss-of-function mutations in the DDB2 gene, which encodes a UV–damaged DNA recognition factor in global genome nucleotide excision repair (GG-NER).

1 Clinical Validity

Based on ClinGen criteria, the DDB2–XP-E association is classified as Moderate, supported by three unrelated probands (one Chinese patient, one Brazilian sibship; 3 probands ([PMID:32228487], [PMID:37573316])) and segregation of the variant in an affected sibling (1 relative ([PMID:37573316])). Concordant functional data across multiple studies further justify this classification.

2 Genetic Evidence

Inheritance is autosomal recessive. Three probands carried two distinct DDB2 variants: a homozygous frameshift c.111_112del (p.Ala39GlufsTer6) in a Chinese patient and a homozygous missense c.1027G>C (p.Ala343Pro) in Brazilian siblings. Segregation analysis confirmed the missense variant in one affected relative. Variant spectrum includes one predicted loss-of-function deletion and one pathogenic missense affecting the DNA-binding domain.

3 Functional / Experimental Evidence

Mechanistic studies demonstrate that DDB2 is essential for UV lesion binding and initiation of GG-NER. Overexpression of human DDB2 in V79 cells enhanced removal of UV-induced photoproducts by >50% within 12 h and conferred resistance to UV-induced apoptosis ([PMID:12553360]). In vitro reconstitution showed that the Cul4A–DDB1 E3 ligase directly ubiquitylates DDB2; the patient-derived p.Lys244Glu variant retains ubiquitylation but disrupts lesion recognition ([PMID:15811626]). UV-induced SUMOylation at Lys309 regulates DDB2 chromatin release; SUMO-deficient mutants show impaired CPD repair ([PMID:28981631]). Collectively, these assays confirm loss-of-function of XP-E variants and DDB2’s pivotal role in UV-damage recognition.

4 Integration & Conclusion

Biallelic DDB2 mutations cause XP-E via haploinsufficiency of UV–damaged DNA recognition, leading to defective GG-NER and skin cancer susceptibility. The limited number of probands reflects the rarity of XP-E, yet consistent functional deficits in patient variants underpin a moderate level of clinical validity. Sun protection and early molecular diagnosis are critical for management.

Key Take-home: DDB2 genetic testing should be prioritized in adult-onset XP-E to inform diagnosis, guide sun-safety measures, and enable genetic counseling.

References

• 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
• BMC medical genomics • 2023 • Brazilian XP-E siblings carrying a novel DDB2 variant developed early-onset melanoma: a case report. PMID:37573316
• Chang Gung medical journal • 2002 • Overexpression of damaged-DNA-binding protein 2 (DDB2) potentiates UV resistance in hamster V79 cells. PMID:12553360
• DNA repair • 2005 • DDB2, the xeroderma pigmentosum group E gene product, is directly ubiquitylated by Cullin 4A-based ubiquitin ligase complex. PMID:15811626
• Carcinogenesis • 2017 • UV radiation-induced SUMOylation of DDB2 regulates nucleotide excision repair. PMID:28981631

Evidence Based Scoring (AI generated)