has participated as a clinical investigator for Zogenix, GW Pharma, Marinius Pharmaceuticals and Vitaflo. She has been a member of advisory boards and speaker for Eisai, GW Pharma, Nutricia and Zogenix. All remuneration has been made to her department.
The MIT Faculty has made this article openly available. Please share how this access benefits you. Your story matters. CitationHamilton, V.E., et al., "Evidence for widespread hydrated minerals on asteroid (101955) Bennu." Nature astronomy 3, 4 (2019): p.
Nemaline myopathy (NM) is a common form of congenital myopathy, affecting approximately 1 in 50,000 individuals, and is defined by the presence of nonprogressive generalized muscle weakness and numerous electron-dense protein inclusions (nemaline bodies or rods) in skeletal myofibers (1). The most severely affected Nemaline myopathy (NM) is a genetic muscle disorder characterized by muscle dysfunction and electron-dense protein accumulations (nemaline bodies) in myofibers. Pathogenic mutations have been described in 9 genes to date, but the genetic basis remains unknown in many cases. Here, using an approach that combined whole-exome sequencing (WES) and Sanger sequencing, we identified homozygous or compound heterozygous variants in LMOD3 in 21 patients from 14 families with severe, usually lethal, NM. LMOD3 encodes leiomodin-3 (LMOD3), a 65-kDa protein expressed in skeletal and cardiac muscle. LMOD3 was expressed from early stages of muscle differentiation; localized to actin thin filaments, with enrichment near the pointed ends; and had strong actin filament-nucleating activity. Loss of LMOD3 in patient muscle resulted in shortening and disorganization of thin filaments. Knockdown of lmod3 in zebrafish replicated NM-associated functional and pathological phenotypes. Together, these findings indicate that mutations in the gene encoding LMOD3 underlie congenital myopathy and demonstrate that LMOD3 is essential for the organization of sarcomeric thin filaments in skeletal muscle.
Nemaline myopathy (NEM) is a common congenital myopathy. At the very severe end of the NEM clinical spectrum are genetically unresolved cases of autosomal-recessive fetal akinesia sequence. We studied a multinational cohort of 143 severe-NEM-affected families lacking genetic diagnosis. We performed whole-exome sequencing of six families and targeted gene sequencing of additional families. We identified 19 mutations in KLHL40 (kelch-like family member 40) in 28 apparently unrelated NEM kindreds of various ethnicities. Accounting for up to 28% of the tested individuals in the Japanese cohort, KLHL40 mutations were found to be the most common cause of this severe form of NEM. Clinical features of affected individuals were severe and distinctive and included fetal akinesia or hypokinesia and contractures, fractures, respiratory failure, and swallowing difficulties at birth. Molecular modeling suggested that the missense substitutions would destabilize the protein. Protein studies showed that KLHL40 is a striated-muscle-specific protein that is absent in KLHL40-associated NEM skeletal muscle. In zebrafish, klhl40a and klhl40b expression is largely confined to the myotome and skeletal muscle, and knockdown of these isoforms results in disruption of muscle structure and loss of movement. We identified KLHL40 mutations as a frequent cause of severe autosomal-recessive NEM and showed that it plays a key role in muscle development and function. Screening of KLHL40 should be a priority in individuals who are affected by autosomal-recessive NEM and who present with prenatal symptoms and/or contractures and in all Japanese individuals with severe NEM.
Objective: To identify causative genes for centronuclear myopathies (CNM), a heterogeneous group of rare inherited muscle disorders that often present in infancy or early life with weakness and hypotonia, using next-generation sequencing of whole exomes and genomes.Methods: Whole-exome or -genome sequencing was performed in a cohort of 29 unrelated patients with clinicopathologic diagnoses of CNM or related myopathy depleted for cases with mutations of MTM1, DNM2, and BIN1. Immunofluorescence analyses on muscle biopsies, splicing assays, and gel electrophoresis of patient muscle proteins were performed to determine the molecular consequences of mutations of interest.Results: Autosomal recessive compound heterozygous truncating mutations of the titin gene, TTN, were identified in 5 individuals. Biochemical analyses demonstrated increased titin degradation and truncated titin proteins in patient muscles, establishing the impact of the mutations.Conclusions: Our study identifies truncating TTN mutations as a cause of congenital myopathy that is reported as CNM. Unlike the classic CNM genes that are all involved in excitation-contraction coupling at the triad, TTN encodes the giant sarcomeric protein titin, which forms a myofibrillar backbone for the components of the contractile machinery. This study expands the phenotypic spectrum associated with TTN mutations and indicates that TTN mutation analysis should be considered in cases of possible CNM without mutations in the classic CNM genes.
Objective The cyclin‐dependent kinase like 5 (CDKL5) gene is a known cause of early onset developmental and epileptic encephalopathy, also known as CDKL5 deficiency disorder (CDD). We sought to (1) provide a description of seizure types in patients with CDD, (2) provide an assessment of the frequency of seizure‐free periods and cortical visual impairment (CVI), (3) correlate these features with genotype and gender, and (4) correlate these features with developmental milestones. Methods This is a cohort study of patients with CDD. Phenotypic features were explored and correlated with gene variant grouping and gender. A developmental score was created based on achieving seven primary milestones. Phenotypic variables were correlated with the developmental score to explore markers of better developmental outcomes. Multivariate linear regression was used to account for age at last visit. Results Ninety‐two patients with CDD were seen during the enrollment period. Eighteen were male (19%); median age at last visit was 5 years (interquartile range = 2.0‐11.0). Eighty‐one percent of patients developed epileptic spasms, but only 47% of those also had hypsarrhythmia. Previously described hypermotor‐tonic‐spasms sequence was seen in only 24% of patients, but 56% of patients had seizures with multiple phases (often tonic and spasms). Forty‐three percent of patients experienced a seizure‐free period ranging from 1 to >12 months, but only 6% were still seizure‐free at the last visit. CVI was present in 75% of all CDD patients. None of these features was associated with genotype group or gender. CVI was correlated with reduced milestone achievement after adjusting for age at last visit and a history of hypsarrhythmia. Significance The most common seizure types in CDD are epileptic spasms (often without hypsarrhythmia) and tonic seizures that may cluster together. CVI is a common feature in CDD and is correlated with achieving fewer milestones.
Christensen, P. R.; Drouet d'Aubigny, C. Y.; Hamilton, V. E.; Reuter, D. C.; Rizk, B.; Simon, A. A.; Asphaug, E.; Bandfield, J. L.; Barnouin, O. S.; Barucci, M. A.; Bierhaus, E. B.; Binzel, R. P.; Bottke, W. F.; Bowles, N. E.; Campins, H.; Clark, B. C.; Clark, B. E.; Connolly, H. C.; Daly, M. G.; Leon, J. de; Delbo', M.; Deshapriya, J. D. P.; Elder, C. M.; Fornasier, S.; Hergenrother, C. W.; Howell, E. S.; Jawin, E. R.; Kaplan, H. H.; Kareta, T. R.; Le Corre, L.; Li, J.-Y.; Licandro, J.; Lim, L. F.; Michel, P.; Molaro, J.; Nolan, M. C.; Pajola, M.; Popescu, M.; Garcia, J. L. Rizos; Ryan, A.; Schwartz, S. R.; Shultz, N.; Siegler, M. A.; Smith, P. H.; Tatsumi, E.; Thomas, C. A.; Walsh, K. J.; Wolner, C. W. V.; Zou, X.-D. and Lauretta, D. S. (2019). Properties of rubble-pile asteroid (101955) Bennu from OSIRIS-REx imaging and thermal analysis. Nature Astronomy, 3 pp. 341-351. For guidance on citations see FAQs.Length of main text: 2956 words Length of methods: 3605 words Length of legends: 565 words Number of references: 53 main text, 69 including methods and supplementary information (refs 67 to 69 are cited in the SI only) , we show that asteroid (101955) Bennu's surface is globally rough, dense with boulders and low in albedo. The number of boulders is surprising given Bennu's moderate thermal inertia, suggesting that simple models linking thermal inertia to particle size do not adequately capture the complexity relating these properties. At the same time, we find evidence for a wide range of particle sizes with distinct albedo characteristics. Our findings imply that ages of Bennu's surface particles span from the disruption of the asteroid's parent body (boulders) to recent in situ production (micron-scale particles).
Centronuclear myopathies (CNMs) are characterized by muscle weakness and increased numbers of central nuclei within myofibers. X-linked myotubular myopathy, the most common severe form of CNM, is caused by mutations in MTM1, encoding myotubularin (MTM1), a lipid phosphatase. To increase our understanding of MTM1 function, we conducted a yeast two-hybrid screen to identify MTM1-interacting proteins. Striated muscle preferentially expressed protein kinase (SPEG), the product of SPEG complex locus (SPEG), was identified as an MTM1-interacting protein, confirmed by immunoprecipitation and immunofluorescence studies. SPEG knockout has been previously associated with severe dilated cardiomyopathy in a mouse model. Using whole-exome sequencing, we identified three unrelated CNM-affected probands, including two with documented dilated cardiomyopathy, carrying homozygous or compound-heterozygous SPEG mutations. SPEG was markedly reduced or absent in two individuals whose muscle was available for immunofluorescence and immunoblot studies. Examination of muscle samples from Speg-knockout mice revealed an increased frequency of central nuclei, as seen in human subjects. SPEG localizes in a double line, flanking desmin over the Z lines, and is apparently in alignment with the terminal cisternae of the sarcoplasmic reticulum. Examination of human and murine MTM1-deficient muscles revealed similar abnormalities in staining patterns for both desmin and SPEG. Our results suggest that mutations in SPEG, encoding SPEG, cause a CNM phenotype as a result of its interaction with MTM1. SPEG is present in cardiac muscle, where it plays a critical role; therefore, individuals with SPEG mutations additionally present with dilated cardiomyopathy.
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