Emerging pathogenic pathways in the spinocerebellar ataxias.

The spinocerebellar ataxias (SCAs) are diseases characterized by neurodegeneration of the spinocerebellum. To date, 28 autosomal dominant SCAs have been described and seventeen causative genes identified. These genes play a role in a broad range of cellular processes.

Characterization of the zebrafish atxn1/axh gene family.

In mammals, ataxin-1 (ATXN1) is a member of a family of proteins in which each member contains an AXH domain. Expansion of the polyglutamine tract in ATXN1 causes the neurodegenerative disease, spinocerebellar ataxia type 1 (SCA1) with prominent cerebellar pathology. Toward a further characterization of the genetic diversification of the ATXN1/AXH gene family, we identified and characterized members of this gene family in zebrafish, a lower vertebrate with a cerebellum.

Precocious osteoarthritis in a family with recurrent COL2A1 mutation.

Objective: To examine the genotypic and phenotypic characteristics of a Micronesian kindred with autosomal dominant precocious osteoarthritis (OA).

Methods: We reviewed records and radiographs of 3 index patients and their parents, administered questionnaires to 16 additional kindred members, performed whole-genome scans of 24 family members, and sequenced relevant genes from 16 family members.

Results: The kindred displayed early onset OA, enlarged epiphyses, platyspondyly, and brachydactyly with dysplastic findings consistent with mild spondyloepiphyseal dysplasia.

QTL mapping in a mouse model of cardiomyopathy reveals an ancestral modifier allele affecting heart function and survival.

The progression from myocardial hypertrophy to heart failure is a complex process, involving genetic and environmental factors. Elucidating the genetic components contributing to heart failure has been difficult, largely because of the heterogeneity of human populations. We have employed a strategy to map genetic loci that modify the heart failure phenotype in a transgenic mouse model of cardiomyopathy caused by cardiac-specific overexpression of calsequestrin.

Multiple quantitative trait loci modify the heart failure phenotype in murine cardiomyopathy.

The variability in outcome of heart failure patients depends on a number of factors including differences in their genetic background. To identify novel genes that modify the human heart failure phenotype, we used a strategy of quantitative trait locus (QTL) mapping in an experimental mouse model of dilated cardiomyopathy induced by cardiac-specific overexpression of calsequestrin and characterized by a strong strain-specific variability in the phenotype. We identified two novel QTLs, Hrtfm3 (heart failure modifier 3) on chromosome (Chr) 4 and Hrtfm4 on Chr 18, significantly linked to survival with likelihood ratio statistics (LRS) of 19.

Genetic modifier loci affecting survival and cardiac function in murine dilated cardiomyopathy.

Background: Understanding the role for genetic factors in human heart failure is difficult because environmental factors cannot be standardized and genetic variation is great. One approach to identify genes that modify disease outcome is to use mouse models that show strong genetic variation of the disease phenotype.

Methods And Results: In this study, we used transgenic mice that develop severe dilated cardiomyopathy due to the cardiac-specific overexpression of calsequestrin.