Three novel missense variants in two families with JAG2-associated limb-girdle muscular dystrophy.

Limb-girdle muscular dystrophy recessive 27 is associated with biallelic variants in JAG2, encoding the JAG2 notch ligand. Twenty-four affected individuals from multiple families have been described in two reports. We present two Australian families with three novel JAG2 missense variants: (c.1021G>T, p.(Gly341Cys)) homozygous in two siblings of Pakistani origin, and compound heterozygous variants (c.703T>C, p.(Trp235Arg); c.2350C>T, p.(Arg784Cys)) in a proband of European ancestry. Patients presented with childhood-onset limb-girdle-like myopathy with difficulty or inability walking. MRI revealed widespread torso and limb muscle involvement. Muscle pathology showed myopathic changes with fatty infiltration. Muscle RNA sequencing revealed significant downregulation of myogenesis genes PAX7, MYF5, and MEGF10 similar to previous JAG2-related muscular dystrophy cases or Jag2-knockdown cells. In absence of functional assays to characterise JAG2 variants, clinical, MRI and transcriptomic profiling collectively may help discern JAG2-related muscular dystrophy, diagnosis of which is essential for patients and families given the severity of disease and reoccurrence risk.

Reduced Protein Import via TIM23 SORT Drives Disease Pathology in TIMM50-Associated Mitochondrial Disease.

TIMM50 is a core subunit of the TIM23 complex, the mitochondrial inner membrane translocase responsible for the import of pre-sequence-containing precursors into the mitochondrial matrix and inner membrane. Here we describe a mitochondrial disease patient who is homozygous for a novel variant in TIMM50 and establish the first proteomic map of mitochondrial disease associated with TIMM50 dysfunction. We demonstrate that TIMM50 pathogenic variants reduce the levels and activity of endogenous TIM23 complex, which significantly impacts the mitochondrial proteome, resulting in a combined oxidative phosphorylation (OXPHOS) defect and changes to mitochondrial ultrastructure. Using proteomic data sets from TIMM50 patient fibroblasts and a TIMM50 HEK293 cell model of disease, we reveal that laterally released substrates imported via the TIM23SORT complex pathway are most sensitive to loss of TIMM50. Proteins involved in OXPHOS and mitochondrial ultrastructure are enriched in the TIM23SORT substrate pool, providing a biochemical mechanism for the specific defects in TIMM50-associated mitochondrial disease patients. These results highlight the power of using proteomics to elucidate molecular mechanisms of disease and uncovering novel features of fundamental biology, with the implication that human TIMM50 may have a more pronounced role in lateral insertion than previously understood.

Comparison of two approaches to measuring clean faces as part of the facial cleanliness component of the SAFE trachoma elimination strategy.

BACKGROUND: The Alliance for the Global Elimination of Trachoma (GET) endorses the full SAFE strategy to eliminate trachoma; Surgery (for trichiasis), Antibiotics (to reduce the community pool of infection, Facial cleanliness, and Environmental improvement (to decrease transmission). There is no accepted measure of facial cleanliness. This study compared two possible metrics for facial cleanliness. METHOD/FINDINGS: Metric one: Clean face was defined as observed absence of ocular and nasal discharge on the face. Metric two: observing a grade of dirtiness (scale 10 = lightest to 0 = darkest) on a standard facial wipe. The reliability of grading a child's face or grading a facial wipe was determined in children in Kongwa Tanzania. We also observed both measurements in a cohort of 202 children ages 1 to <7years prior to face cleaning, immediately afterwards, and 4 hours afterwards. Fifty of the children did not have face cleaning and were controls. Intra-and interobserver reliability was similar for both measures, the latter = 0.53 for observing a clean face and 0.52 for grading a facial wipe. There was no correlation between the two. Both measures detected facial cleaning, compared to control children who were not cleaned, immediately after cleaning; control children with 53% clean faces and wipe score of 6.7 compared to cleaned children with 88% clean faces and wipe score of 8 (p = .0001, p = < .0001, respectively). Both measures also detected face washing 4 hours previously compared to controls. CONCLUSIONS: The two metrics were equally reliable, and both measured the behavior of face washing. They measure different aspects of a clean face; one measures the amount of dirt on wiped area and the other measures ocular and nasal discharge. Both measurements appear to capture the behavior of facial cleaning, and the choice of metric would appear to rest on the measurement that captures the stated objective of the behavior, consideration of costs, training, logistics, and implementation.