Loss of the human BRIP1 C terminus does not cause Fanconi anemia.

BRIP1

The N-terminal BRIP1 helicase domain (amino acids 1-888) is required and sufficient for interstrand crosslink resistance; the sensitivity seen with p.Lys998GlufsTer60 stems from the aberrant frameshift extension, not from C-terminal truncation

The authors report 11 individuals from 7 families homozygous for one of two C-terminally truncating BRIP1 variants (previously FANCJ): c.2947del (p.Ile983LeufsTer2, n = 3) or c.2992_2995del (p.Lys998GlufsTer60, n = 8). None showed haematological manifestations of Fanconi anaemia: no bone marrow failure, myelodysplasia or Fanconi-associated early-onset cancer. Patient blood cells carrying p.Ile983LeufsTer2 kept a stable protein and were resistant to crosslinking agents, whereas p.Lys998GlufsTer60 caused partial protein degradation and a mild cellular phenotype, recapitulated in an isogenic knockout model. Introducing a stop codon at position 998 (p.Lys998Ter) yielded a stable, resistant protein, showing that the aberrant frameshift extension, rather than C-terminal truncation, causes the sensitivity; the helicase domain (amino acids 1-888) is required and sufficient, and BRCA1 interaction via phosphorylated Ser990 is dispensable.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

A directly useful result for interpretation: a homozygous truncating variant at the C-terminal end of BRIP1 should not be reported as a Fanconi anaemia diagnosis on the basis of truncation alone. The paper is a reminder that the rule 'truncating = loss of function' depends on position and actual protein consequence, and that two neighbouring frameshifts can have different effects. The cancer risk associated with these alleles is not addressed in the abstract.

Analysis by Dr Thibaut Benquey