UBE2T – Fanconi Anemia

The current evidence demonstrates a strong association between UBE2T and Fanconi anemia. Multiple independent case reports and multi‐patient studies have identified biallelic pathogenic variants in UBE2T in patients presenting with classical features of Fanconi anemia, including bone marrow failure and genomic instability (PMID:26119737, PMID:26046368).

Genetic studies have identified several loss‐of‐function and missense variants that disrupt UBE2T function. Notably, a recurrent variant, c.4C>G (p.Gln2Glu), along with frameshift alleles like c.368dup (p.Leu124fs), have been reported in unrelated individuals. These findings, derived from at least 4 independent probands (PMID:26046368), underscore a consistent autosomal recessive inheritance pattern.

Despite limited quantitative segregation data, the identification of biallelic mutations in unrelated families suggests robust segregation of the variant with disease phenotype. The absence of FANCD2 and FANCI monoubiquitination in patient fibroblasts, which is rescued by exogenous wild‐type UBE2T, further supports the deleterious impact of these alleles (PMID:26119737).

Functional studies provide compelling mechanistic support for UBE2T’s role in the Fanconi anemia pathway. Complementation assays in patient-derived cells have demonstrated that UBE2T deficiency leads to impaired activation of FANCD2 and FANCI, thereby hampering the DNA interstrand crosslink repair process. These findings have been consistently replicated across multiple independent studies (PMID:26119737, PMID:26046368).

Integration of genetic and functional evidence indicates that pathogenic UBE2T variants disrupt a critical ubiquitination step required for maintaining genomic integrity. The convergence of reported biallelic loss-of-function mutations and demonstrable cellular dysfunction establishes UBE2T as a bona fide contributor to Fanconi anemia pathogenesis.

Key take‑home: Testing for UBE2T variants can serve as a reliable molecular diagnostic tool for Fanconi anemia, guiding clinical decision‑making and offering avenues for targeted therapeutic investigation.

References

• Cell reports • 2015 • Deficiency of UBE2T, the E2 Ubiquitin Ligase Necessary for FANCD2 and FANCI Ubiquitination Causes FA-T Subtype of Fanconi Anemia PMID:26119737
• Human molecular genetics • 2015 • AluY-mediated germline deletion, duplication and somatic stem cell reversion in UBE2T defines a new subtype of Fanconi anemia PMID:26085575
• American journal of human genetics • 2015 • Mutations in the gene encoding the E2 conjugating enzyme UBE2T cause Fanconi anemia PMID:26046368

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