Myozenin 2 Is a Novel Gene for Human Hypertrophic Cardiomyopathy

Abstract

Hypertrophic cardiomyopathy (HCM) is a genetic disorder caused by mutations in sarcomeric proteins (excluding phenocopy). The causal genes in approximately one-third of the cases remain unknown. We identified a family comprised of 6 clinically affected members. The phenotype was characterized by early onset of symptoms, pronounced cardiac hypertrophy, and cardiac arrhythmias. We excluded MYH7, MYBPC3, TNNT2, and ACTC1 as the causal gene either by direct sequencing or by haplotype analysis. To map the putative candidate sarcomeric gene, we perforbold locusspecific haplotyping to detect cosegregation of the locus haplotype with the phenotype, followed by mutation screening. We genotyped 5 short-tandem-repeat markers that spanned a 4.4-centimorgan region on 4q26-q27 locus and encompassed myozenin 2 (MYOZ2), a Z-disk protein. The maximum logarithm of odds score was 2.03 (P‫.)500.0؍‬ All affected members shared a common haplotype, implicating MYOZ2 as the causal gene. To detect the causal mutation, we sequenced all exons and exon-intron boundaries of MYOZ2 in 10 family members and identified a T3 C missense mutation corresponding to S48P substitution, which cosegregated with inheritance of HCM (N‫.)6؍‬ It was absent in 4 clinically normal family members and in 658 additional normal individuals. To determine frequency of the MYOZ2 mutations in HCM, we sequenced MYOZ2 in 516 HCM probands and detected another missense mutation (I246M). It was absent in 2 normal family members and 517 controls. Both mutations affect highly conserved amino acids. We conclude MYOZ2 is a novel causal gene for human HCM.

Stargazing microRNA maps a new miR-21 star for cardiac hypertrophy

“…Interestingly, release of SORBS2 from damaged cardiac tissue into the bloodstream upon fatal acute myocardial infarction has been described recently (23). PDLIM5 is highly conserved across species and, like SORBS2, colocalizes at Z-disks and is directly associated with dilated cardiomyopathy (24) and indirectly involved in human hypertrophic cardiomyopathy (25). Collectively, these findings raise the question of whether miR-21* plays a role in the development of HF in Z-disk disruption models.…”

Mutations in filamin C cause a new form of familial hypertrophic cardiomyopathy

“…From these gene variants, we searched for those predicted to affect the function of the protein and presenting cardiac-specific expression, with the finding that FLNC-encoding the muscle-specific filamin C and implicated in myocyte differentiation-had a missense mutation in this patient (p.A1539T). This filamin is localized at the Z-discs of the sarcomere and interacts with other sarcomeric proteins, including myozenin-2 and myotilin 10,11 . To further evaluate the possibility that FLNC could be a novel gene associated with familial HCM, we next analysed whether the FLNC variant identified in this patient segregated with the disease in this family.…”

Prevalence of Sarcomere Protein Gene Mutations in Preadolescent Children With Hypertrophic Cardiomyopathy

“…In this study, we did not screen every gene implicated in familial HCM, and so it is quite possible that mutations in genes such as titin 22 and myozenin, 23 or even genes such as LAMP-2 associated with Danon disease 24,25 or PTPN11 associated with Noonan syndrome, 26 could explain some of the remaining idiopathic cases. However, most studies suggest that these account for only a very small number of cases.…”