Gain-of-Function Mutation in STIM1 (P.R304W) Is Associated with Stormorken Syndrome.

Stormorken syndrome is a rare autosomal dominant disorder characterized by a phenotype that includes miosis, thrombocytopenia/thrombocytopathy with bleeding time diathesis, intellectual disability, mild hypocalcemia, muscle fatigue, asplenia, and ichthyosis. Using targeted sequencing and whole-exome sequencing, we identified the c.910C > T transition in a STIM1 allele (p.R304W) only in patients and not in their unaffected family members. STIM1 encodes stromal interaction molecule 1 protein (STIM1), which is a finely tuned endoplasmic reticulum Ca(2+) sensor. The effect of the mutation on the structure of STIM1 was investigated by molecular modeling, and its effect on function was explored by calcium imaging experiments. Results obtained from calcium imaging experiments using transfected cells together with fibroblasts from one patient are in agreement with impairment of calcium homeostasis. We show that the STIM1 p.R304W variant may affect the conformation of the inhibitory helix and unlock the inhibitory state of STIM1. The p.R304W mutation causes a gain of function effect associated with an increase in both resting Ca(2+) levels and store-operated calcium entry. Our study provides evidence that Stormorken syndrome may result from a single-gene defect, which is consistent with Mendelian-dominant inheritance.

Characterization of a new V gene replacement in the absence of activation-induced cytidine deaminase and its contribution to human B-cell receptor diversity.

In B cells, B-cell receptor (BCR) immunoglobulin revision is a common route for modifying unwanted antibody specificities via a mechanism called VH replacement. This in vivo process, mostly affecting heavy-chain rearrangement, involves the replacement of all or part of a previously rearranged IGHV gene with another germline IGHV gene located upstream. Two different mechanisms of IGHV replacement have been reported: type 1, involving the recombination activating genes complex and requiring a framework region 3 internal recombination signal; and type 2, involving an unidentified mechanism different from that of type 1. In the case of light-chain loci, BCR immunoglobulin editing ensures that a second V-J rearrangement occurs. This helps to maintain tolerance, by generating a novel BCR with a new antigenic specificity. We report that human B cells can, surprisingly, undergo type 2 replacement associated with κ light-chain rearrangements. The de novo IGKV-IGKJ products result from the partial replacement of a previously rearranged IGKV gene by a new germline IGKV gene, in-frame and without deletion or addition of nucleotides. There are wrcy/rgyw motifs at the 'IGKV donor-IGKV recipient chimera junction' as described for type 2 IGHV replacement, but activation-induced cytidine deaminase (AID) expression was not detected. This unusual mechanism of homologous recombination seems to be a variant of gene conversion-like recombination, which does not require AID. The recombination phenomenon described here provides new insight into immunoglobulin locus recombination and BCR immunoglobulin repertoire diversity.

Prospective evaluation of the familial prevalence of the brugada syndrome.

The familial prevalence of Brugada syndrome (BrS) in a consecutive series of patients was prospectively determined. BrS is genetically determined with autosomal dominant transmission. The familial prevalence of the BrS is unknown. A detailed pedigree of each family of patients with BrS was assembled and permission was obtained to invite relatives for electrocardiography and an ajmaline challenge. Sixty-two of 98 patients participated in the study and were included over a 6-year period. SCN5A genotyping was performed in 56 of these 62 patients (90%). Electrocardiograms (ECGs) of 488 relatives (mean age 38 ± 20 years, 45% men) were recorded and 270 of these relatives agreed to undergo an ajmaline challenge. Spontaneous type 1 BrS ECG was found in 4 of 488 relatives (0.8%). In the group of relatives in whom ajmaline challenge was performed (n = 270), the finding was positive in 79 subjects (29%). SCN5A genotyping identified 5 other affected relatives. As a result, the total number of affected relatives was 88. Standard 12-lead ECG was normal in 64 of the 88 affected relatives (73%). Mean percentage of affected relatives per family was 27 ± 32% (95% confidence interval 19 to 35). Familial forms of BrS were observed in 41 of the 62 families (66%) and no SCN5A mutations were found in sporadic forms. In conclusion, after active family screening affected relatives were found in almost 1/3 of subjects. BrS appeared to be a familial disease in 2/3 of subjects.