ClinVar

In 6 unrelated Chinese women (families 1, 2, 4, 5, 7, and 10) with preimplantation embryo arrest (OZEMA17; 620319), Wang et al. (2023) identified homozygosity for a c.607C-T transition (c.607C-T, NM_001145715.3) in the KPNA7 gene, resulting in a leu203-to-pro (L203P) substitution. Another 3 women with the same phenotype were compound heterozygous for L203P and another mutation in KPNA7: the proband in family 3 had a c.635C-T transition, resulting in a pro212-to-leu (P212L; 614107.0004); the proband in family 6 had a c.523C-A transversion, resulting in a gln175-to-lys (Q175K; 614107.0005); and the proband in family 9 had a 7-bp deletion (c.1350_1356delGTGTCTT; 614107.0006), causing a frameshift predicted to result in a premature termination codon (Cys451Ter; C451X). The mutations segregated fully with disease in the 8 families for which relatives' DNA was available, and none was found in 2,813 controls. The Q175K variant and the 7-bp deletion were not found in the ExAC or gnomAD databases, but the L203F variant was present at minor allele frequencies of 1.41 X 10(-4) and 3.21 x 10(-4), respectively, and the P212L at MAFs of 4.75 x 10(-5) and 6.02 x 10(-5). Western blot of transfected HEK293T cells showed that all mutant protein levels were significantly lower than wildtype KPNA7. KPNA7-SV40TNLS interaction was strongly disrupted by the missense variants, and mutant KPNA7 showed significantly reduced SV40TNLS protein transport activity compared to wildtype KPNA7. In addition, GST-RSL1D1 (615874)-GFP pulldown and immunoprecipitation experiments demonstrated impaired interaction between the mutant proteins and the KPNA7 substrate RSL1D1.