Novel pathogenic VPS13A gene mutations in Japanese patients with chorea-acanthocytosis.

OBJECTIVE: To identify mutations in vacuolar protein sorting 13A (VPS13A) for Japanese patients with suspected chorea-acanthocytosis (ChAc). METHODS: We performed a comprehensive mutation screen, including sequencing and copy number variation (CNV) analysis of the VPS13A gene, and chorein Western blotting of erythrocyte ghosts. As the results of the analysis, 17 patients were molecularly diagnosed with ChAc. In addition, we investigated the distribution of VPS13A gene mutations and clinical symptoms in a total of 39 molecularly diagnosed Japanese patients with ChAc, including 22 previously reported cases. RESULTS: We identified 11 novel pathogenic mutations, including 1 novel CNV. Excluding 5 patients with the unknown symptoms, 97.1% of patients displayed various neuropsychiatric symptoms or forms of cognitive dysfunction during the course of disease. The patients carrying the 2 major mutations representing over half of the mutations, exon 60-61 deletion and exon 37 c.4411C>T (R1471X), were localized in western Japan. CONCLUSIONS: We identified 13 different mutations in VPS13A, including 11 novel mutations, and verified the clinical manifestations in 39 Japanese patients with ChAc.

Novel pathogenic XK mutations in McLeod syndrome and interaction between XK protein and chorein.

OBJECTIVE: To identify XK pathologic mutations in 6 patients with suspected McLeod syndrome (MLS) and a possible interaction between the chorea-acanthocytosis (ChAc)- and MLS-responsible proteins: chorein and XK protein. METHODS: Erythrocyte membrane proteins from patients with suspected MLS and patients with ChAc, ChAc mutant carriers, and normal controls were analyzed by XK and chorein immunoblotting. We performed mutation analysis and XK immunoblotting to molecularly diagnose the patients with suspected MLS. Lysates of cultured cells were co-immunoprecipitated with anti-XK and anti-chorein antibodies. RESULTS: All suspected MLS cases were molecularly diagnosed with MLS, and novel mutations were identified. The average onset age was 46.8 ± 8 years, which was older than that of the patients with ChAc. The immunoblot analysis revealed remarkably reduced chorein immunoreactivity in all patients with MLS. The immunoprecipitation analysis indicated a direct or indirect chorein-XK interaction. CONCLUSIONS: In this study, XK pathogenic mutations were identified in all 6 MLS cases, including novel mutations. Chorein immunoreactions were significantly reduced in MLS erythrocyte membranes. In addition, we demonstrated a possible interaction between the chorein and XK protein via molecular analysis. The reduction in chorein expression is similar to that between Kell antigens and XK protein, although the chorein-XK interaction is a possibly noncovalent binding unlike the covalent Kell-XK complex. Our results suggest that reduced chorein levels following lack of XK protein are possibly associated with molecular pathogenesis in MLS.