Deleterious variants in TRAK1 disrupt mitochondrial movement and cause fatal encephalopathy

Cellular distribution and dynamics of mitochondria are regulated by several motor proteins and a microtubule network. In neurons, mitochondrial trafficking is crucial because of high energy needs and calcium ion buffering along axons to synapses during neurotransmission. The trafficking kinesin proteins (TRAKs) are well characterized for their role in lysosomal and mitochondrial trafficking in cells, especially neurons. Using whole exome sequencing, we identified homozygous truncating variants in TRAK1 (NM_001042646:c.287-2A > C), in six lethal encephalopathic patients from three unrelated families. The pathogenic variant results in aberrant splicing and significantly reduced gene expression at the RNA and protein levels. In comparison with normal cells, TRAK1-deficient fibroblasts showed irregular mitochondrial distribution, altered mitochondrial motility, reduced mitochondrial membrane potential, and diminished mitochondrial respiration. This study confirms the role of TRAK1 in mitochondrial dynamics and constitutes the first report of this gene in association with a severe neurodevelopmental disorder

Oral monosaccharide therapies to reverse renal and muscle hyposialylation in a mouse model of GNE myopathy

Abstract. To improve solution robustness, we introduce the concept of super solutions to constraint programming. An (a, b)-super solution is one in which if a variables lose their values, the solution can be repaired by assigning these variables with a new values and at most b other variables. Super solutions are a generalization of supermodels in propositional satisfiability. We focus in this paper on (1,0)-super solutions, where if one variable loses its value, we can find another solution by re-assigning this variable with a new value. To find super solutions, we explore methods based both on reformulation and on search. Our reformulation methods transform the constraint satisfaction problem so that the only solutions are super solutions. Our search methods are based on a notion of super consistency. Experiments show that super MAC, a novel search-based method shows considerable promise. When super solutions do not exist, we show how to find the most robust solution. Finally, we extend our approach from robust solutions of constraint satisfaction problems to constraint optimization problems.

Combination of common mtDNA variants results in mitochondrial dysfunction and a connective tissue dysregulation

Mitochondrial dysfunction can be associated with a range of clinical manifestations. Here, we report a family with a complex phenotype including combinations of connective tissue, neurological, and metabolic symptoms that were passed on to all surviving children. Analysis of the maternally inherited mtDNA revealed a novel genotype encompassing the haplogroup J - defining mitochondrial DNA (mtDNA) ND5 m.13708G>A (A458T) variant arising on the mtDNA haplogroup H7A background, an extremely rare combination. Analysis of transmitochondrial cybrids with the 13708A-H7 mtDNA revealed a lower mitochondrial respiration, increased reactive oxygen species production (mROS), and dysregulation of connective tissue gene expression. The mitochondrial dysfunction was exacerbated by histamine, explaining why all eight surviving children inherited the dysfunctional histidine decarboxylase allele (W327X) from the father. Thus, certain combinations of common mtDNA variants can cause mitochondrial dysfunction, mitochondrial dysfunction can affect extracellular matrix gene expression, and histamine-activated mROS production can augment the severity of mitochondrial dysfunction. Most important, we have identified a previously unreported genetic cause of mitochondrial disorder arising from the incompatibility of common, nonpathogenic mtDNA variants