Genetic Insights from Consanguineous Cardiomyopathy Families.

Inherited cardiomyopathies are a prevalent cause of heart failure and sudden cardiac death. Both hypertrophic (HCM) and dilated cardiomyopathy (DCM) are genetically heterogeneous and typically present with an autosomal dominant mode of transmission. Whole exome sequencing and autozygosity mapping was carried out in eight un-related probands from consanguineous Middle Eastern families presenting with HCM/DCM followed by bioinformatic and co-segregation analysis to predict the potential pathogenicity of candidate variants. We identified homozygous missense variants in TNNI3K, DSP, and RBCK1 linked with a dilated phenotype, in NRAP linked with a mixed phenotype of dilated/hypertrophic, and in KLHL24 linked with a mixed phenotype of dilated/hypertrophic and non-compaction features. Co-segregation analysis in family members confirmed autosomal recessive inheritance presenting in early childhood/early adulthood. Our findings add to the mutational spectrum of recessive cardiomyopathies, supporting inclusion of KLHL24, NRAP and RBCK1 as disease-causing genes. We also provide evidence for novel (recessive) modes of inheritance of a well-established gene TNNI3K and expand our knowledge of the clinical heterogeneity of cardiomyopathies. A greater understanding of the genetic causes of recessive cardiomyopathies has major implications for diagnosis and screening, particularly in underrepresented populations, such as those of the Middle East.

Reconstitution of a functional human thymus by postnatal stromal progenitor cells and natural whole-organ scaffolds.

The thymus is a primary lymphoid organ, essential for T cell maturation and selection. There has been long-standing interest in processes underpinning thymus generation and the potential to manipulate it clinically, because alterations of thymus development or function can result in severe immunodeficiency and autoimmunity. Here, we identify epithelial-mesenchymal hybrid cells, capable of long-term expansion in vitro, and able to reconstitute an anatomic phenocopy of the native thymus, when combined with thymic interstitial cells and a natural decellularised extracellular matrix (ECM) obtained by whole thymus perfusion. This anatomical human thymus reconstruction is functional, as judged by its capacity to support mature T cell development in vivo after transplantation into humanised immunodeficient mice. These findings establish a basis for dissecting the cellular and molecular crosstalk between stroma, ECM and thymocytes, and offer practical prospects for treating congenital and acquired immunological diseases.

Diverse species-specific phenotypic consequences of loss of function sorting nexin 14 mutations.

Mutations in the SNX14 gene cause spinocerebellar ataxia, autosomal recessive 20 (SCAR20) in both humans and dogs. Studies implicating the phenotypic consequences of SNX14 mutations to be consequences of subcellular disruption to autophagy and lipid metabolism have been limited to in vitro investigation of patient-derived dermal fibroblasts, laboratory engineered cell lines and developmental analysis of zebrafish morphants. SNX14 homologues Snz (Drosophila) and Mdm1 (yeast) have also been conducted, demonstrated an important biochemical role during lipid biogenesis. In this study we report the effect of loss of SNX14 in mice, which resulted in embryonic lethality around mid-gestation due to placental pathology that involves severe disruption to syncytiotrophoblast cell differentiation. In contrast to other vertebrates, zebrafish carrying a homozygous, maternal zygotic snx14 genetic loss-of-function mutation were both viable and anatomically normal. Whilst no obvious behavioural effects were observed, elevated levels of neutral lipids and phospholipids resemble previously reported effects on lipid homeostasis in other species. The biochemical role of SNX14 therefore appears largely conserved through evolution while the consequences of loss of function varies between species. Mouse and zebrafish models therefore provide valuable insights into the functional importance of SNX14 with distinct opportunities for investigating its cellular and metabolic function in vivo.

Risk factors for cartilage damage and osteoarthritis of the elbow joint: case-control study and systematic literature review.

INTRODUCTION: This case-control study compares patients with healthy elbows to a group of symptomatic patients with cartilage damage/osteoarthritis. MATERIALS AND METHODS: The control group (n = 126) was recruited during routine medical examinations of patients (general medical offices). Included in the case group were a total of 92 patients who were undergoing arthroscopy as a result of chronic elbow discomfort. All patients were questioned with regard to occupational stress and athletic stress. RESULTS: A significantly increased risk of cartilage damage/osteoarthritis was found with subjectively perceived increased stress in occupational settings: OR = 3.8 (95% CI 2.1-6.7); p < 0.001; for the individual stresses of the elbow joint in occupational settings, the following severities in effects were found: Exposure to heavy work OR = 3.9 (95% CI 2.2-6.8); Force OR = 3.7 (95% CI 2.1-6.5); Vibration OR = 4.6 (95% CI 2.5-8.5); Repetition OR = 9.2 (95% CI 3.6-23.3); p < 0.001. Elbow-stressing sport types represent a potential risk factor for the development of cartilage damage/osteoarthritis of the elbow joint: OR = 2.5 (95% CI 1.3-4.7); p = 0.003. CONCLUSIONS: Cartilage damage/radiographic osteoarthritis of the elbow joint are rare with respect to the overall prevalence of osteoarthritis. In the large number of patients with cartilage damage/radiographic osteoarthritis of the elbow joint, occupational or athletic stress factors and injuries sustained, in addition to other causes (rheumatism, gout), can prove as possible causes of these as secondary to symptomatic forms of osteoarthritis.