AlphaB-crystallin mutations cause hypertrophic and dilated cardiomyopathy
Familial hypertrophic cardiomyopathy (FHC)is caused by mutations in >10 genes coding for the proteins of the sarcomere. Mutations in some of these genes also cause dilated cardiomyopathy (DCM). Recently, the chaperone protein alphaB-crystallin, coded for by the gene CRYAB, has been shown to stabilise desmin, titin, actin and myosin-binding protein C when cardiomyocytes are stressed, e.g. during ischemia. A missense mutation in CRYAB, R120G, has been shown to cause desmin-related cardiomyopathy in humans and cardiac failure in transgenic mice. In such mice the cardiomyopathy is characterised by aggregation of desmin and alphaB-crystallin. Thus, CRYAB is a candidate gene for cardiomyopathy. We screened the CRYAB gene for mutations in 100 patients with FHC and 100 patients with DCM and identified two probands heterozygous for the N-terminal mutations, Q26X and P39L, in HCM and one proband heterozygous for a c-terminal mutation, S154G, in DCM. None of the mutations were found in 350 normal controls. As the Q26X mutation cause a protein truncation and most likely haploinsufficiency, and the proline in pos 39 is a helix-breaker reducing compactness of the N-terminal domain and, most likely, thereby supporting chaperone function, the mechanism of HCM is probably reduced alphaB-crystallin production or chaperone function. None of the patients har myopathic symptoms and none had mutations in other HCM associated genes. This is the first study demonstrating that CRYAB is a gene where mutations cause HCM and it also directs the attention to other proteins involved in maintaining the stability of the sarcomere, when looking for new candidate genes. The Q26X mutation occured spontaneously and the patient died from sudden cardiac death. The CRYAB gene is thus also a candidate when looking for the cause of sudden death.