title: Non-coding VMA21 deletions cause X-linked myopathy with excessive autophagy.
abstract: X-linked Myopathy with Excessive Autophagy (XMEA) affects proximal muscles of the lower extremities and follows a progressive course reminiscent of muscular dystrophy. It is caused by mutations in VMA21 whose protein product assembles lysosomes' proton pumps. All XMEA mutations to date have been single-nucleotide substitutions that reduce VMA21 expression, which leads to modest lysosomal pH increase, the first step in the disease's pathogenesis. We now report a new class of XMEA mutations. We identified two VMA21 non-coding microdeletions, one intronic (c.54-16_54-8del), the other in the 3'UTR (c.*13_*104del). Both resulted in a relatively more severe (early ambulation loss), diffuse (extra-ocular and upper extremity involvement), and early (neonatal) onset disease compared to previously reported patients. Our cases highlight the importance of including non-coding regions of VMA21 in genetic testing panels of dystrophies and myopathies. Specific diagnosis of XMEA will be particularly important as therapies aimed at correcting the modest rise in lysosomal pH at the root of this disease are developed.
authors: Neuromuscular Disease and Immunology, Fondazione IRCCS Istituto Neurologico "C. Besta", Milan, Italy; Department of Paediatrics (Neurology) and Program in Genetics and Genome Biology, The Hospital for Sick Children and University of Toronto, Toronto, Canada.
authors: A
authors: A
authors: Ruggieri
authors: Department of Paediatrics (Neurology) and Program in Genetics and Genome Biology, The Hospital for Sick Children and University of Toronto, Toronto, Canada.
authors: N
authors: N
authors: Ramachandran
authors: Department of Paediatrics (Neurology) and Program in Genetics and Genome Biology, The Hospital for Sick Children and University of Toronto, Toronto, Canada.
authors: P
authors: P
authors: Wang
authors: SA Clinical Genetics Service, SA Pathology, Adelaide, Australia; School of Paediatrics and Reproductive Health, The University of Adelaide, Adelaide, Australia.
authors: E
authors: E
authors: Haan
authors: Department of Neurology, Royal Adelaide Hospital, Adelaide, Australia.
authors: C
authors: C
authors: Kneebone
authors: Hanson Institute Centre for Neurological Diseases, SA Pathology, Adelaide, Australia.
authors: J
authors: J
authors: Manavis
authors: Neuromuscular Disease and Immunology, Fondazione IRCCS Istituto Neurologico "C. Besta", Milan, Italy.
authors: L
authors: L
authors: Morandi
authors: Child Neurology Units, Fondazione IRCCS Istituto Neurologico "C. Besta", Milan, Italy.
authors: I
authors: I
authors: Moroni
authors: Hanson Institute Centre for Neurological Diseases, SA Pathology, Adelaide, Australia; Department of Pathology, University of Adelaide, Adelaide, Australia.
authors: P
authors: P
authors: Blumbergs
authors: Neuromuscular Disease and Immunology, Fondazione IRCCS Istituto Neurologico "C. Besta", Milan, Italy.
authors: M
authors: M
authors: Mora
authors: Department of Paediatrics (Neurology) and Program in Genetics and Genome Biology, The Hospital for Sick Children and University of Toronto, Toronto, Canada. Electronic address: berge.minassian@sickkids.ca.
authors: B A
authors: BA
authors: Minassian
mesh_terms: D000293:Adolescent; D001343:Autophagy / Q000235:genetics; D001921:Brain / Q000473:pathology / Q000503:physiopathology; D040181:Genetic Diseases, X-Linked / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D018482:Muscle, Skeletal / Q000473:pathology; D009135:Muscular Diseases / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D012333:RNA, Messenger / Q000378:metabolism; D017384:Sequence Deletion; D025262:Vacuolar Proton-Translocating ATPases / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: D012333:RNA, Messenger; C540401:VMA21 protein, human; D025262:Vacuolar Proton-Translocating ATPases
keywords: Autophagy; Lysosomal ATPase; Microdeletions; VMA21; XMEA