@article {978, title = {POGLUT1 biallelic mutations cause myopathy with reduced satellite cells, α-dystroglycan hypoglycosylation and a distinctive radiological pattern.}, journal = {Acta Neuropathol}, volume = {139}, year = {2020}, month = {2020 03}, pages = {565-582}, abstract = {

Protein O-glucosyltransferase 1 (POGLUT1) activity is critical for the Notch signaling pathway, being one of the main enzymes responsible for the glycosylation of the extracellular domain of Notch receptors. A biallelic mutation in the POGLUT1 gene has been reported in one family as the cause of an adult-onset limb-girdle muscular dystrophy (LGMD R21; OMIM$\#$ 617232). As the result of a collaborative international effort, we have identified the first cohort of 15 patients with LGMD R21, from nine unrelated families coming from different countries, providing a reliable phenotype-genotype and mechanistic insight. Patients carrying novel mutations in POGLUT1 all displayed a clinical picture of limb-girdle muscle weakness. However, the age at onset was broadened from adult to congenital and infantile onset. Moreover, we now report that the unique muscle imaging pattern of "inside-to-outside" fatty degeneration observed in the original cases is indeed a defining feature of POGLUT1 muscular dystrophy. Experiments on muscle biopsies from patients revealed a remarkable and consistent decrease in the level of the NOTCH1 intracellular domain, reduction of the pool of satellite cells (SC), and evidence of α-dystroglycan hypoglycosylation. In vitro biochemical and cell-based assays suggested a pathogenic role of the novel POGLUT1 mutations, leading to reduced enzymatic activity and/or protein stability. The association between the POGLUT1 variants and the muscular phenotype was established by in vivo experiments analyzing the indirect flight muscle development in transgenic Drosophila, showing that the human POGLUT1 mutations reduced its myogenic activity. In line with the well-known role of the Notch pathway in the homeostasis of SC and muscle regeneration, SC-derived myoblasts from patients{\textquoteright} muscle samples showed decreased proliferation and facilitated differentiation. Together, these observations suggest that alterations in SC biology caused by reduced Notch1 signaling result in muscular dystrophy in LGMD R21 patients, likely with additional contribution from α-dystroglycan hypoglycosylation. This study settles the muscular clinical phenotype linked to POGLUT1 mutations and establishes the pathogenic mechanism underlying this muscle disorder. The description of a specific imaging pattern of fatty degeneration and muscle pathology with a decrease of α-dystroglycan glycosylation provides excellent tools which will help diagnose and follow up LGMD R21 patients.

}, keywords = {Animals, Animals, Genetically Modified, Drosophila melanogaster, Dystroglycans, Female, Genetic Association Studies, Glucosyltransferases, Glycosylation, Humans, Male, Muscle, Skeletal, Muscular Dystrophies, Limb-Girdle, Mutation, Pedigree, Satellite Cells, Skeletal Muscle}, issn = {1432-0533}, doi = {10.1007/s00401-019-02117-6}, author = {Servi{\'a}n-Morilla, E and Cabrera-Serrano, M and Johnson, K and Pandey, A and Ito, A and Rivas, E and Chamova, T and Muelas, N and Mongini, T and Nafissi, S and Claeys, K G and Grewal, R P and Takeuchi, M and Hao, H and B{\"o}nnemann, C and Lopes Abath Neto, O and Medne, L and Brandsema, J and T{\"o}pf, A and Taneva, A and Vilchez, J J and Tournev, I and Haltiwanger, R S and Takeuchi, H and Jafar-Nejad, H and Straub, V and Paradas, Carmen} } @article {911, title = {Sequential targeted exome sequencing of 1001 patients affected by unexplained limb-girdle weakness.}, journal = {Genet Med}, volume = {22}, year = {2020}, month = {2020 09}, pages = {1478-1488}, abstract = {

PURPOSE: Several hundred genetic muscle diseases have been described, all of which are rare. Their clinical and genetic heterogeneity means that a genetic diagnosis is challenging. We established an international consortium, MYO-SEQ, to aid the work-ups of muscle disease patients and to better understand disease etiology.

METHODS: Exome sequencing was applied to 1001 undiagnosed patients recruited from more than 40 neuromuscular disease referral centers; standardized phenotypic information was collected for each patient. Exomes were examined for variants in 429 genes associated with muscle conditions.

RESULTS: We identified suspected pathogenic variants in 52\% of patients across 87 genes. We detected 401 novel variants, 116 of which were recurrent. Variants in CAPN3, DYSF, ANO5, DMD, RYR1, TTN, COL6A2, and SGCA collectively accounted for over half of the solved cases; while variants in newer disease genes, such as BVES and POGLUT1, were also found. The remaining well-characterized unsolved patients (48\%) need further investigation.

CONCLUSION: Using our unique infrastructure, we developed a pathway to expedite muscle disease diagnoses. Our data suggest that exome sequencing should be used for pathogenic variant detection in patients with suspected genetic muscle diseases, focusing first on the most common disease genes described here, and subsequently in rarer and newly characterized disease genes.

}, keywords = {Anoctamins, Exome, Glucosyltransferases, Humans, Muscular Dystrophies, Limb-Girdle, Whole Exome Sequencing}, issn = {1530-0366}, doi = {10.1038/s41436-020-0840-3}, author = {Topf, Ana and Johnson, Katherine and Bates, Adam and Phillips, Lauren and Chao, Katherine R and England, Eleina M and Laricchia, Kristen M and Mullen, Thomas and Valkanas, Elise and Xu, Liwen and Bertoli, Marta and Blain, Alison and Casas{\'u}s, Ana B and Duff, Jennifer and Mroczek, Magdalena and Specht, Sabine and Lek, Monkol and Ensini, Monica and MacArthur, Daniel G and Straub, Volker} } @article {402, title = {Isolated polycystic liver disease genes define effectors of polycystin-1 function.}, journal = {J Clin Invest}, volume = {127}, year = {2017}, month = {2017 May 01}, pages = {1772-1785}, abstract = {

Dominantly inherited isolated polycystic liver disease (PCLD) consists of liver cysts that are radiologically and pathologically identical to those seen in autosomal dominant polycystic kidney disease, but without clinically relevant kidney cysts. The causative genes are known for fewer than 40\% of PCLD index cases. Here, we have used whole exome sequencing in a discovery cohort of 102 unrelated patients who were excluded for mutations in the 2 most common PCLD genes, PRKCSH and SEC63, to identify heterozygous loss-of-function mutations in 3 additional genes, ALG8, GANAB, and SEC61B. Similarly to PRKCSH and SEC63, these genes encode proteins that are integral to the protein biogenesis pathway in the endoplasmic reticulum. We inactivated these candidate genes in cell line models to show that loss of function of each results in defective maturation and trafficking of polycystin-1, the central determinant of cyst pathogenesis. Despite acting in a common pathway, each PCLD gene product demonstrated distinct effects on polycystin-1 biogenesis. We also found enrichment on a genome-wide basis of heterozygous mutations in the autosomal recessive polycystic kidney disease gene PKHD1, indicating that adult PKHD1 carriers can present with clinical PCLD. These findings define genetic and biochemical modulators of polycystin-1 function and provide a more complete definition of the spectrum of dominant human polycystic diseases.

}, keywords = {Adult, Animals, Cell Line, Transformed, Cysts, Endoplasmic Reticulum, Female, Genome-Wide Association Study, Glucosidases, Glucosyltransferases, Heterozygote, Humans, Intracellular Signaling Peptides and Proteins, Liver Diseases, Male, Membrane Proteins, Mice, Mutation, SEC Translocation Channels, TRPP Cation Channels}, issn = {1558-8238}, doi = {10.1172/JCI90129}, author = {Besse, Whitney and Dong, Ke and Choi, Jungmin and Punia, Sohan and Fedeles, Sorin V and Choi, Murim and Gallagher, Anna-Rachel and Huang, Emily B and Gulati, Ashima and Knight, James and Mane, Shrikant and Tahvanainen, Esa and Tahvanainen, Pia and Sanna-Cherchi, Simone and Lifton, Richard P and Watnick, Terry and Pei, York P and Torres, Vicente E and Somlo, Stefan} }