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Nemaline myopathy (NM) is a genetically and clinically heterogeneous disorder resulting from a disruption of the thin filament proteins of the striated muscle sarcomere. The disorder is typically characterized by muscle weakness including the face, neck, respiratory, and limb muscles and is clinically classified based on the age of onset and severity. Mutations in the ACTA1 gene contribute to a significant proportion of NM cases. The majority of ACTA1 gene mutations are missense mutations causing autosomal dominant NM by producing an abnormal protein. However, approximately 10% of ACTA1 gene mutations are associated with autosomal recessive NM; these mutations are associated with loss of protein function. We report the first case of a large deletion in the ACTA1 gene contributing to autosomal recessive NM. This case illustrates the importance of understanding disease mechanisms at the molecular level to accurately infer the inheritance pattern and potentially aid with clinical management., (Copyright © 2014. Published by Elsevier B.V.)

Lowe syndrome is a rare X-linked disorder characterized by bilateral congenital cataracts, renal Fanconi syndrome, and mental retardation. Lowe syndrome results from mutations in the OCRL1 gene, which encodes a phosphatidylinositol 4,5 bisphosphate 5-phosphatase located in the trans-Golgi network. As a first step in identifying the link between ocrl1 deficiency and the clinical disorder, we have identified a reproducible cellular abnormality of the actin cytoskeleton in fibroblasts from patients with Lowe syndrome. The cellular abnormality is characterized by a decrease in long actin stress fibers, enhanced sensitivity to actin depolymerizing agents, and an increase in punctate F-actin staining in a distinctly anomalous distribution in the center of the cell. We also demonstrate an abnormal distribution of two actin-binding proteins, gelsolin and alpha-actinin, proteins regulated by both PIP(2) and Ca(+2) that would be expected to be altered in Lowe cells. Actin polymerization plays a key role in the formation, maintenance, and proper function of tight junctions and adherens junctions, which have been demonstrated to be critical in renal proximal tubule function, and in the differentiation of the lens. These findings point to a general mechanism to explain how this PIP(2) 5-phosphatase deficiency might produce the Lowe syndrome phenotype.