Familial hypertrophic cardiomyopathy has been associated with several mutations in the gene encoding human cardiac troponin I (HCTnI). A missense mutation in the inhibitory region of TnI replaces an arginine residue at position 145 with a glycine and cosegregates with the disease. Results from several assays indicate that the inhibitory function of HCTnI R145G is significantly reduced. When HCTnI R145G was incorporated into whole troponin, Tn R145G (HCTnT⅐HCTnI R145G ⅐HCTnC), only partial inhibition of the actin-tropomyosin-myosin ATPase activity was observed in the absence of Ca 2؉ compared with wild type Tn (HCTnT⅐HCTnI⅐HCTnC). Maximal activation of actin-tropomyosin-myosin ATPase in the presence of Ca 2؉ was also decreased in Tn R145G when compared with Tn. Using skinned cardiac muscle fibers, we determined that in comparison with the wild type complex 1) the complex containing HCTnI R145G only inhibited 84% of Ca 2؉ -unregulated force, 2) the recovery of Ca 2؉ -activated force was decreased, and 3) there was a significant increase in the Ca 2؉ sensitivity of force development. Computer modeling of troponin C and I variables predicts that the primary defect in TnI caused by these mutations would lead to diastolic dysfunction. These results suggest that severe diastolic dysfunction and somewhat decreased contractility would be prominent clinical features and that hypertrophy could arise as a compensatory mechanism. Familial hypertrophic cardiomyopathy (FHC)1 has been linked to mutations in genes of nine different sarcomeric proteins. These mutations have been found in the genes for ␣-myosin heavy chain (1), cardiac myosin essential light chain and cardiac myosin regulatory light chain (2), ␣-tropomyosin, cardiac troponin T (TnT) (3), cardiac myosin-binding protein C (4, 5), troponin I (TnI) (6), ␣-actin (7), as well as titin (8), and possibly troponin C (TnC) (9). This disease has recently gained significant attention due to several highly publicized reports of sudden death and fainting spells in young athletes who were asymptomatic and otherwise healthy individuals. In general, patients with FHC demonstrate an increase in heart muscle mass and sometimes an irregular echocardiogram (10). Kimura et al. (6) reported five missense mutations in TnI, R145G, R145Q, R162W, G203S, and K206Q, that cosegregate with FHC (Fig. 1). Three other TnI FHC mutants (S199N, Lys-183 deletion, and an exon 8 deletion mutant encompassing the stop codon of the cardiac TnI gene) have recently been discovered (11, 12). Functionally TnI is the inhibitory subunit of the troponin (Tn) complex that controls the interaction between actin and myosin in a Ca 2ϩ -dependent manner (13-15). Studies using proteolytic fragments of fast skeletal TnI identified the central TnI sequence (residues 96 -116) as being responsible for its inhibitory activity. Residues 104 -115 of fast skeletal TnI (comparable to residues 136 -147 in cardiac TnI) formed the minimum sequence necessary for inhibition of muscle contraction (16 -19). Two of these mutations occ...

Objective:To identify a causative variant(s) that may contribute to Alzheimer disease (AD) in African Americans (AA) in the ATP-binding cassette, subfamily A (ABC1), member 7 (ABCA7) gene, a known risk factor for late-onset AD.Methods:Custom capture sequencing was performed on ∼150 kb encompassing ABCA7 in 40 AA cases and 37 AA controls carrying the AA risk allele (rs115550680). Association testing was performed for an ABCA7 deletion identified in large AA data sets (discovery n = 1,068; replication n = 1,749) and whole exome sequencing of Caribbean Hispanic (CH) AD families.Results:A 44-base pair deletion (rs142076058) was identified in all 77 risk genotype carriers, which shows that the deletion is in high linkage disequilibrium with the risk allele. The deletion was assessed in a large data set (531 cases and 527 controls) and, after adjustments for age, sex, and APOE status, was significantly associated with disease (p = 0.0002, odds ratio [OR] = 2.13 [95% confidence interval (CI): 1.42–3.20]). An independent data set replicated the association (447 cases and 880 controls, p = 0.0117, OR = 1.65 [95% CI: 1.12–2.44]), and joint analysis increased the significance (p = 1.414 × 10−5, OR = 1.81 [95% CI: 1.38–2.37]). The deletion is common in AA cases (15.2%) and AA controls (9.74%), but in only 0.12% of our non-Hispanic white cohort. Whole exome sequencing of multiplex, CH families identified the deletion cosegregating with disease in a large sibship. The deleted allele produces a stable, detectable RNA strand and is predicted to result in a frameshift mutation (p.Arg578Alafs) that could interfere with protein function.Conclusions:This common ABCA7 deletion could represent an ethnic-specific pathogenic alteration in AD.

Recently, a hexanucleotide repeat expansion in the C9ORF72 gene has been identified to account for a significant portion of Caucasian families affected by frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Given the clinical overlap of FTD with Alzheimer disease (AD), we hypothesized that C9ORF72 expansions may contribute to AD. In Caucasians, we found C9ORF72 expansions in the pathogenic range of FTD/ALS (>30 repeats) at a rate of 0.76% in AD cases versus zero in controls (p=3.3E-03, 1,182 cases, 1,039 controls). In contrast, no large expansions were detected in individuals of African American ethnicity (291 cases, 620 controls). However, in the range of normal variation of C9ORF72 expansions (0–23 repeat copies), we detected significant differences in distribution and mean repeat counts between Caucasians and African Americans. Clinical and pathological reevaluation of identified C9ORF72 expansion carriers revealed nine clinical and/or autopsy confirmed AD and two FTD finial diagnoses. Thus, our results support the notion that large C9ORF72 expansions lead to a phenotypic spectrum of neurodegenerative disease including AD.

African Americans are willing to participate in health-related research studies. Several factors such as the appropriate incentives, community trust building, outreach, and community partnership creation are necessary for engaging minority participants. Incorporating factors that target African American enrollment in research design and implementation, such as increased training of minority health ambassadors and African American researchers and public health specialists, are needed to better engage minorities across generations, in research.