Genetics and phenotypic characteristics of autosomal dominant polycystic kidney disease in Finns.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease, leading to renal insufficiency and renal transplantation. Mutation screening in the major gene for ADPKD, the polycystic kidney disease type 1 (PKD1) gene, has often been incomplete because of multiple homologous copies of this gene elsewhere on chromosome 16. Furthermore, there are only a few studies investigating genotype-phenotype correlations in patients with ADPKD. In this study, we screened the entire coding region of the PKD1 and PKD2 genes in 17 Finnish families with ADPKD via long-range polymerase chain reaction, single-strand conformation polymorphism analysis, and direct sequencing. We were able to identify mutations co-segregating with ADPKD in all 16 families linked to PKD1 by haplotype analysis. Of these mutations, six were insertions/deletions, five nonsense mutations, and five missense mutations. In the only PKD2-linked family, we found a missense mutation, R322Q. With the exception of one mutation (L845S in PKD1), all mutations were novel. Mutations and their location did not have a strong correlation with the phenotype with the exception of subarachnoidal hemorrhage or brain aneurysm, where mutations were located more often at the 5' end of the PKD1 gene than at the 3' end of the PKD1 gene.

Two novel mutations in the beta-myosin heavy chain gene associated with dilated cardiomyopathy.

BACKGROUND: Dilated cardiomyopathy (DCM) is familial in approximately 20-35% of cases of idiopathic DCM. Several mutations in the different sarcomere protein genes have been reported to cause DCM. AIMS: We wanted to investigate the role of sarcomere protein gene variants in Finnish DCM patients. METHODS AND RESULTS: We screened all coding exons of five sarcomere protein genes (beta-myosin heavy chain, alpha-tropomyosin, troponin C, troponin I and troponin T) in a well-characterized population of 52 DCM patients in Eastern Finland by the PCR-SSCP and sequencing method. Two novel mutations, Arg1053Gln and Arg1500Trp, in the beta-myosin heavy chain gene in two index patients were detected. The proband with the Arg1053Gln mutation had a dilated left ventricle and impaired systolic function, but other family members carrying this mutation presented with septal hypertrophy. It thus seems that the Arg1053Gln mutation is primarily a HCM mutation, which can also lead to DCM. The other mutation, Arg1500Trp, was associated with a typical DCM phenotype. The Arg1500Trp mutation carrier had only one family member alive, but she did not carry the mutation and, therefore, cosegregation of the mutation and the disease in this family could not be reliably verified. No disease-causing mutations were found in the other sarcomere protein genes. CONCLUSIONS: Two novel mutations in the beta-myosin heavy chain gene were detected in patients with DCM. Overall, mutations in the beta-myosin heavy chain gene seem to be relatively uncommon in Finnish DCM patients.

A novel mutation, Ser143Pro, in the lamin A/C gene is common in finnish patients with familial dilated cardiomyopathy.

AIMS: The mutations most frequently associated with dilated cardiomyopathy (DCM) have been reported in the lamin A/C gene. The role of variants of the lamin A/C gene was investigated in patients with DCM from eastern and southern Finland. METHODS AND RESULTS: All 12 exons of the lamin A/C gene were screened in 18 well-characterised familial DCM patients from eastern and southern Finland and in 72 sporadic DCM patients from eastern Finland using the PCR-SSCP method. A novel mutation, Ser143Pro (S143P), was detected in the lamin A/C gene in 24 subjects from 5 unrelated families and in one sporadic case of DCM. Sinus or atrioventricular nodal dysfunction occurred in the majority of the affected subjects, many of which required pacemaker implantation. Seven patients (28%) with the S143P mutation died suddenly or from progressive heart failure, or underwent heart transplantation. The haplotypes 5-5-5-3, 5-5-5-2, and 5-5-5-1 co-segregated with the Ser143Pro mutation, suggesting a founder effect of this mutation. CONCLUSIONS: A novel mutation S143P in the lamin A/C gene was found to be common among Finnish DCM patients. Haplotype analysis strongly suggests a founder effect of this mutation. The phenotype is characterised by severe heart failure, progressive atrioventricular conduction defects, and sudden death. Screening for the lamin A/C gene and, particularly, the S143P mutation seems warranted when patients with DCM have conduction system disturbances.

Genetics of hypertrophic cardiomyopathy in eastern Finland: few founder mutations with benign or intermediary phenotypes.

Hypertrophic cardiomyopathy (HCM) is a genetically and clinically heterogeneous myocardial disease caused by mutations in genes encoding sarcomeric proteins. To assess the genetic background and phenotypic expression of HCM in eastern Finland, we screened 35 unrelated patients with HCM from the Kuopio University Hospital area for variants in 9 genes encoding sarcomeric proteins with the PCR-SSCP method. We herewith describe our previous findings in five sarcomeric genes and also report hitherto unpublished data on four additional sarcomeric genes. Mutations in the cardiac myosin-binding protein C gene (MYBPC3) were most frequent, accounting for 26% of cases. A novel mutation (Gln1061X) in this gene was the most common mutation, found in 6 of 35 families and accounting for 17% of all cases. Other novel mutations in MYBPC3 (IVS5-2A --> C, IVS14-13G --> A, and Ex25deltaLys) were found in one family each. A previously described alpha-tropomyosin (TPM1) mutation (Asp175Asn) was found in 11% of cases. Haplotype analysis suggested that the two most common variants (MYBPC3-Gln1061X and TPM1-Asp175Asn) were founder mutations. Only one mutation (Arg719Trp) in the beta-myosin heavy chain gene (MYH7) was found in one family, and no disease-causing mutations were found in the genes encoding alpha-actin, cardiac troponin I, T, C, or myosin essential and regulatory light chains. Altogether, the aforementioned 6 mutations found in MYBPC3, TPM1, and MYH7 accounted for 61% of familial and 40% of all HCM cases. The mutations were associated mostly with benign or intermediary phenotypes with only few HCM-related deaths. We conclude that the genetic profile of HCM in eastern Finland is unique, characterized by few founder mutations with benign or intermediary phenotypes.

A novel mutation, Arg71Thr, in the delta-sarcoglycan gene is associated with dilated cardiomyopathy.

Approximately 20-35% of cases of idiopathic dilated cardiomyopathy are familial. DCM-associated mutations have been reported in 13 genes including the desmin, delta-sarcoglycan, and metavinculin genes. This study screened for variants in these genes in Finnish patients with DCM. All coding regions of the desmin and delta-sarcoglycan genes and the metavinculin-specific exon of the vinculin gene were screened in 52 DCM patients from eastern Finland by PCR-SSCP. We detected a novel mutation, Arg71Thr, in the delta-sarcoglycan gene in two members of a small DCM family. One of the mutation carriers fulfills diagnostic criteria for DCM and is also symptomatic. The other mutation carrier has slightly dilated left ventricle and well preserved systolic function. Therefore carriers of the Arg71Thr mutation had a relatively mild phenotype and a late onset of the disease. Disease-associated mutations were not found in the desmin gene or the metavinculin-specific exon of the vinculin gene. We conclude that the desmin and delta-sarcoglycan genes are not predominant disease-causing genes in patients with DCM in eastern Finland.

Progression of kidney disease varies between families with defects in the polycystic kidney disease type 1 gene in eastern Finland.

OBJECTIVE: To characterize, for the first time, the phenotype and clinical course of autosomal dominant polycystic kidney disease (ADPKD) in Finnish patients. MATERIAL AND METHODS: All patients underwent an abdominal sonographic examination and most of those with ADPKD underwent magnetic resonance angiography of the head. Haplotype analysis was used to classify 20 ADPKD families into those with defects in either the polycystic kidney disease type 1 (PKD1) or polycystic kidney disease type 2 (PKD2) genes. Evaluation of the rate of progression of kidney disease in patients with ADPKD was based on creatinine values. RESULTS: Haplotype analysis showed that 16 families had defects in the PKD1 gene and one had defects in the PKD2 gene. Three families were excluded because of uninformative haplotypes. The final study population consisted of 79 unaffected family members, 109 patients with defects in the PKD1 gene and 10 with defects in the PKD2 gene. Higher prevalences of hepatic cysts (3% in healthy relatives, 60% in PKD1 patients and 90% in PKD2 patients; p < 0.001), subarachnoid hemorrhage or cerebral aneurysms (1%, 12% and 0%, respectively; p < 0.001), proteinuria (1%, 23% and 0%, respectively; p < 0.001) and hematuria (5%, 30% and 0%, respectively; p < 0.001) were found in PKD1 patients compared to the healthy relatives. PKD1 patients had a faster progression of kidney disease than PKD2 patients (p < 0.001). The progression of kidney disease varied substantially among the PKD1 families. CONCLUSION: The relative proportions of PKD1 and PKD2 patients and the phenotype of ADPKD were similar in our Finnish patients compared to previous studies in other populations. However, the progression of kidney disease differed substantially among PKD1 families, indicating a heterogeneic genetic background of PKD1 in Finnish patients.

Insulin resistance is related to left ventricular hypertrophy in patients with polycystic kidney disease type 1.

BACKGROUND: Left ventricular hypertrophy (LVH) is common in patients with autosomal dominant polycystic kidney disease (ADPKD). Although insulin resistance contributes to cardiac hypertrophy, the relationship between insulin resistance and LVH in patients with ADPKD has not been previously studied. METHODS: We performed M-mode and color Doppler echocardiography on 176 family members (106 patients and 70 healthy relatives) from 16 families with polycystic kidney disease type 1 (PKD1). Left ventricular mass index (LVMI) was calculated using the Penn equation and corrected for body surface area. Fasting insulin and glucose concentrations were measured and insulin resistance was evaluated by means of the homeostasis model assessment. RESULTS: In multivariate regression analysis, insulin resistance was significantly associated with LVMI in healthy relatives (P < 0.01) and patients with PKD1 (P < 0.05) independent of age, weight, systolic blood pressure, and albuminuria. CONCLUSION: Insulin resistance is associated with LVMI in patients with PKD1 independently of other factors known to increase LVMI.

Promoter polymorphisms -359T/C and -303A/G of the catalytic subunit p110beta gene of human phosphatidylinositol 3-kinase are not associated with insulin secretion or insulin sensitivity in finnish subjects.

OBJECTIVE: Phosphatidylinositol (PI) 3-kinase activity is required for insulin-stimulated translocation of GLUT4 transporters and glucose uptake and utilization. Therefore, genes encoding the subunits of PI 3-kinase are promising candidate genes for insulin resistance and type 2 diabetes. We recently cloned the catalytic subunit p110beta gene of human PI 3-kinase and reported two nucleotide polymorphisms, -359T/C and -303A/G, in the promoter region of this gene. In this study, we determined the effects of these polymorphisms on insulin secretion and insulin sensitivity. RESEARCH DESIGN AND METHODS: We studied two separate groups of Finnish nondiabetic subjects. Insulin secretion was evaluated by intravenous glucose tolerance test and insulin sensitivity by hyperinsulinemic-euglycemic clamp. RESULTS: Our results showed that the -359T/C and -303A/G polymorphisms did not have a significant effect on fasting plasma insulin levels, insulin secretion, or insulin sensitivity. CONCLUSIONS: It is unlikely that the promoter polymorphisms -359T/C and -303A/G of the catalytic subunit p110beta gene of human PI 3-kinase have a major impact on insulin secretion, insulin sensitivity, or the risk of type 2 diabetes in Finnish subjects.

Mutations in the cardiac myosin-binding protein C gene are the predominant cause of familial hypertrophic cardiomyopathy in eastern Finland.

Hypertrophic cardiomyopathy (HCM) is a genetic disorder characterized by cardiac hypertrophy caused by mutations in genes encoding sarcomere proteins. This study screened all patients with HCM from the Kuopio University Hospital region in eastern Finland for variants in the cardiac myosin-binding protein C gene ( MYBPC3). All 35 exons of MYBPC3 were screened by the single-strand conformation polymorphism method in 37 unrelated patients with HCM. In MYBPC3 we identified seven novel (Gln1061X, IVS5-2A-->C, IVS14-13G-->A, Ex25DeltaLys, Pro147Leu, Ser236Gly, and Arg1138His) and two previously reported (Arg326Gln, Val896Met) variants, all of which are predicted to affect the structure of the encoded protein. Four of the nine variants, a nonsense mutation Gln1061X, a splice acceptor mutation (IVS5-2A-->C), a novel substitution in intron 14 (IVS14-13G-->A), and a novel 3-bp deletion in exon 25 (Ex25DeltaLys) were concluded to be disease-causing mutations because they cosegregated with the HCM phenotype or were absent in more than 200 normal chromosomes, or both. The mutation Gln1061X was found most frequently, being present in 6 families (23 subjects) while the other three mutations were found in single families each. Haplotype analysis indicated a likely founder effect among the families carrying the Gln1061X mutation. We found four novel mutations in MYBPC3, accounting for approx. 38% of familial and 24% of all cases of HCM. In our previous and unpublished studies no more frequent cause of HCM has been found in genetic analyses of other eight sarcomeric proteins. Consequently MYBPC3 is the predominant gene for HCM in eastern Finland. In addition, several amino acid substitutions in MYBPC3 suspected to be not associated with HCM were identified, indicating that some of the missense variants found in MYBPC3 are possibly not disease-causing mutations.

No variants in the cardiac actin gene in Finnish patients with dilated or hypertrophic cardiomyopathy.

BACKGROUND: Dilated and hypertrophic cardiomyopathies are primary myocardial diseases that cause considerable morbidity and mortality. Although these cardiomyopathies are clinically heterogeneous, genetic factors play an important role in their etiology and pathogenesis. The defects in the cardiac actin (ACTC) gene can cause both cardiomyopathies. The aim of our study was to screen for variants in the ACTC gene in patients with dilated or hypertrophic cardiomyopathy from Eastern Finland. MATERIALS AND METHODS: Altogether, 32 patients with dilated and 40 patients with hypertrophic cardiomyopathy were included in the study. Commonly approved diagnostic criteria were applied, and secondary cardiomyopathies were carefully excluded. All 6 exons of the ACTC gene were amplified with polymerase chain reaction and screened for variants with single-strand conformation polymorphism analysis. RESULTS AND CONCLUSION: We did not find any new or previously reported variants. Our results indicate that defects in the ACTC gene do not explain dilated cardiomyopathy or hypertrophic cardiomyopathy in subjects from Eastern Finland and confirm earlier results that the ACTC gene does not play an important role in the genetics of dilated or hypertrophic cardiomyopathies.