Homozygous mutation of desmocollin-2 in arrhythmogenic right ventricular cardiomyopathy with mild palmoplantar keratoderma and woolly hair.

OBJECTIVES: The phenotypic triad of arrhythmogenic right ventricular cardiomyopathy (ARVC) associated with palmoplantar keratoderma and woolly hair has been previously associated with homozygous mutations in both plakoglobin and desmoplakin, which are both critical components of the desmosome. We present here a clinical and genetic study of a consanguineous pedigree in which 2 siblings present with ARVC with left ventricular involvement and associated mild palmoplantar keratoderma and woolly hair. METHODS: Clinical evaluation of the 2 patients and their family members was undertaken along with a homozygosity-mapping approach to identify the relevant gene and sequencing analysis to identify the causative mutation. RESULTS: The homozygosity-mapping approach excluded the involvement of both plakoglobin and desmoplakin in this pedigree. However, an extended region of homozygosity in both affected cases was revealed at the chromosome 18 desmocollin/desmoglein cluster, genes which encode components of the desmosome. Sequence analysis of the democollin-2 gene, located within this cluster, revealed a homozygous single-base deletion in exon 12 (1841delG). This mutation is predicted to lead to a frame shift and a premature termination codon at position 625 (S614fsX625). CONCLUSIONS: This is the first reported case of a mutation in desmocollin-2 associated with autosomal recessive ARVC.

Homozygous mutation of MYBPC3 associated with severe infantile hypertrophic cardiomyopathy at high frequency among the Amish.

BACKGROUND: Familial hypertrophic cardiomyopathy (HCM) is a leading cause of sudden cardiac death among young and apparently healthy people. Autosomal dominant mutations within genes encoding sarcomeric proteins have been identified. An autosomal recessive form of HCM has been discovered in a group of Amish children that is associated with poor prognosis and death within the first year of life. Affected patients experienced progressive cardiac failure despite maximal medical treatment. Postmortem histology showed myofibre disarray and myocyte loss consistent with refractory clinical deterioration in affected infants. OBJECTIVE: To conduct a genome-wide screen for linkage and try to identify an autozygous region which cosegregates with the infant cardiac phenotype METHODS AND RESULTS: An autozygous region of chromosome 11 which cosegregates with the infant cardiac phenotype was identified. This region contained the MYBPC3 gene, which has previously been associated with autosomal dominant adult-onset HCM. Sequence analysis of the MYBPC3 gene identified a splice site mutation in intron 30 which was homozygous in all affected infants. All surviving patients with the homozygous MYBPC3 gene mutations (3330+2T>G) underwent an orthotopic heart transplantation. CONCLUSIONS: Homozygous mutations in the MYBPC3 gene have been identified as the cause of severe infantile HCM among the Amish population.

The natural history of Noonan syndrome: a long-term follow-up study.

OBJECTIVE: To define better the adult phenotype and natural history of Noonan syndrome. DESIGN: A prospective observational study of a large cohort. RESULTS: Data are presented for 112 individuals with Noonan syndrome (mean age 25.3 (range 12-71) years), who were followed up for a mean of 12.02 years. Mutations in PTPN11 were identified in 35% of probands. Ten subjects died during the study interval; three of these deaths were secondary to heart failure associated with hypertrophic cardiomyopathy. Pulmonary stenosis affected 73 (65%) subjects; 42 (58%) required no intervention, nine underwent balloon pulmonary valvuloplasty (three requiring further intervention) and 22 surgical valvuloplasty (three requiring further intervention). Hypertrophic cardiomyopathy affected 21 (19%) patients, which had remitted in two cases, but one subject required cardiac transplant. No subjects died suddenly or had symptoms suggestive of arrhythmia. The mean final adult height was 167.4 cm in males and 152.7 cm in females. Feeding problems in infancy were identified as a predictor of future outcome. The mean age of speaking in two-word phrases was 26 months for those with no feeding difficulties, compared with 39 months for those with severe problems requiring nasogastric feeding. Attendance at a school for children with special needs for the same groups was 12.5% and 58%, respectively. A statement of special educational need had been issued in 44% overall; however, academic achievement was broadly similar to that of the general population. IMPLICATIONS: Although the morbidity for some patients with Noonan syndrome is low, early predictors of poorer outcome have been identified, which will help ascertain those most in need of intervention.

Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome.

Noonan syndrome (MIM 163950) is an autosomal dominant disorder characterized by dysmorphic facial features, proportionate short stature and heart disease (most commonly pulmonic stenosis and hypertrophic cardiomyopathy). Webbed neck, chest deformity, cryptorchidism, mental retardation and bleeding diatheses also are frequently associated with this disease. This syndrome is relatively common, with an estimated incidence of 1 in 1,000-2,500 live births. It has been mapped to a 5-cM region (NS1) [corrected] on chromosome 12q24.1, and genetic heterogeneity has also been documented. Here we show that missense mutations in PTPN11 (MIM 176876)-a gene encoding the nonreceptor protein tyrosine phosphatase SHP-2, which contains two Src homology 2 (SH2) domains-cause Noonan syndrome and account for more than 50% of the cases that we examined. All PTPN11 missense mutations cluster in interacting portions of the amino N-SH2 domain and the phosphotyrosine phosphatase domains, which are involved in switching the protein between its inactive and active conformations. An energetics-based structural analysis of two N-SH2 mutants indicates that in these mutants there may be a significant shift of the equilibrium favoring the active conformation. This implies that they are gain-of-function changes and that the pathogenesis of Noonan syndrome arises from excessive SHP-2 activity.

Mapping of the human insulin receptor substrate-2 gene, identification of a linked polymorphic marker and linkage analysis in families with Type II diabetes: no evidence for a major susceptibility role.

Insulin receptor substrate 2 (IRS-2) is a substrate of the insulin receptor and mediates the action of the insulin. Disruption of the IRS-2 gene in mice results in peripheral insulin resistance and relative insulin deficiency. It is therefore possible that defects in the IRS-2 gene contribute to Type II (non-insulin-dependent) diabetes mellitus. We have examined the gene for evidence of linkage to Type II diabetes in Ashkenazi Jewish families. Radiation hybrid panel mapping was used to refine the map position of the IRS-2 gene and, in the absence of polymorphic markers within the gene, to identify nearby markers. The IRS-2 gene was placed 23cR from the marker D13S1265 on chromosome 13q34. 200 affected sib-pairs were genotyped for three markers across the region. Nonparametric linkage analysis (GENEHUNTER) used with this data found no evidence of excess allele sharing in the IRS-2 gene region. We therefore concluded that variation in the IRS-2 gene is unlikely to contribute to Type II diabetes in this discrete Caucasian population.

A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome).

Wolfram syndrome (WFS; OMIM 222300) is an autosomal recessive neurodegenerative disorder defined by young-onset non-immune insulin-dependent diabetes mellitus and progressive optic atrophy. Linkage to markers on chromosome 4p was confirmed in five families. On the basis of meiotic recombinants and disease-associated haplotypes, the WFS gene was localized to a BAC/P1 contig of less than 250 kb. Mutations in a novel gene (WFS1) encoding a putative transmembrane protein were found in all affected individuals in six WFS families, and these mutations were associated with the disease phenotype. WFS1 appears to function in survival of islet beta-cells and neurons.