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Collagen XII-related disease (COL12 -RD), also classified as myopathic Ehlers-Danlos syndrome (EDS), is a congenital onset disorder with overlapping connective tissue and muscle involvement. Biallelic loss-of-function (LoF), as well as dominantly acting monoallelic variants in COL12A1 , have been recognized to cause COL12 -RD. While there have been additional reports of patients with dominant COL12A1 variants, fewer cases of the presumed more severe recessive COL12 -RD have been documented. We present clinical, immunocytochemical, and imaging data on eight additional patients from seven families, with biallelic variants in COL12A1. All patients presented with a consistent constellation of symptoms including congenital onset disease characterized by hypotonia, dysmorphic features including most notably gingival hypertrophy, prominent distal joint hyperlaxity with co-occurring contractures of large joints, and muscle involvement of variable degrees, evident both clinically and on muscle imaging. Five patients presented with a severe congenital phenotype manifesting with profound weakness, significantly delayed or minimal attainment of motor milestones, respiratory insufficiency, and feeding difficulties. Three patients presented with milder disease manifesting with mild to moderate muscle weakness and delayed milestones but were able to achieve independent ambulation. Patients were found to have biallelic LoF COL12A1 variants, except for one family with compound heterozygosity for a missense variant (p.I1393Ffs*11/ p.A1110D). Consistent with the variable clinical spectrum, in vitro collagen XII immunocytochemistry analysis in fibroblasts ranged from complete absence of collagen XII expression in a patient with severe disease, to a mild reduction in a patient with milder disease. This series aids to further establish COL12A1 as a recessive myopathic EDS gene and to expand the clinical spectrum to include a milder EDS phenotype. [ABSTRACT FROM AUTHOR]

Recent improvements in thermoelectric (TE) materials have expanded the potential to use this technology to generate electricity from waste heat in a variety of applications and the performance of the TE generator improves when the temperature difference across the generator is as large as possible given the constraints associated with its application. A thermal switch is used, located physically between the heat source and the TE device, to modulate the heat flow through the TE device.

The Wilms tumor suppressor gene (wt1) is required for kidney development and has been shown to modulate cell growth. However, the downstream targets of wt1 that mediate growth suppression have not been elucidated. RbAp46 is coexpressed with wt1 in E13.5 metanephric mesenchyme and its expression is upregulated by wt1 in human embryonic kidney (293) cells. Similar to wt1, RbAp46 inhibits colony formation 2-3x in transfected cells. We investigated the mechanism of growth suppression in stable cell lines that constitutively express RbAp46. Compared with control cells, RbAp46-expressing cells exhibited a reduced proliferation index (22 vs 40%) and accumulated in G2-M of the cell cycle (34 vs 21% ). A leucine to phenylalanine mutation in the fifth WD domain of LIN-53, a Caenorhabditis elegans RbAp46/48 orthologue, has a dominant negative effect on vulva induction. Since this leucine is conserved in RbAp46, we tested the effects of this mutation (L299F) on cell growth. In contrast to wild-type RbAp46, cells expressing the RbAp46(L299F) mutant did not exhibit reduced proliferation (43 vs 40%) and did not accumulate in G2-M (18 vs 21%) compared to control cells. Coexpression of the L299F mutant in cells that express wild-type RbAp46 at levels sufficient to cause growth suppression prevented G2-M arrest and restored the growth curve and proliferation index to control levels, consistent with dominant negative activity. We conclude that RbAp46 is a potentially important downstream mediator of growth inhibition by wt1 and that a conserved leucine in the fifth WD domain is required for its effects on the cell cycle.