RESUMEN
Biallelic pathogenic variants in INPP5K have been associated with a rare congenital muscular dystrophy that presents with muscle weakness, short stature, intellectual disability, and early-onset cataracts. A characteristic pattern of muscle involvement has been identified on muscle MRI in a small case series, including involvement of the vasti, anterior tibialis, and peronei with relative sparing of the rectus femoris, sartorius, and gracilis muscles. This case describes a patient who initially presented in infancy with hypotonia, motor delays, and short stature. She was eventually diagnosed at almost 3 years with INPP5K-related muscular dystrophy after extensive workup that included multiple subspecialist evaluations, genetic testing for non-neuromuscular disorders, and a muscle biopsy. Muscle ultrasound (MUS) was performed at the end of this diagnostic journey, which demonstrated characteristic features that supported the diagnosis, including notable involvement of the vasti muscles with sparing of the rectus femoris. This case highlights how MUS can be a useful tool in the evaluation of children for neuromuscular disorders. MUS can help refine the differential and guide further steps in evaluation when performed early in the diagnostic process and may help clarify interpretation of genetic testing results when performed later.
Asunto(s)
Músculo Esquelético , Ultrasonografía , Humanos , Femenino , Ultrasonografía/métodos , Músculo Esquelético/diagnóstico por imagen , Músculo Esquelético/patología , Distrofias Musculares/genética , Distrofias Musculares/diagnóstico por imagen , PreescolarRESUMEN
Pathogenic variants in LMNA have been associated with a wide spectrum of muscular conditions: the laminopathies. LMNA-related congenital muscular dystrophy is a laminopathy characterised by the early onset of symptoms and often leads to a fatal outcome at young ages. Children face a heightened risk of malignant arrhythmias. No established paediatric protocols for managing this condition are available. We review published cases and provide insights into disease progression in two twin sisters with LMNA-related muscular dystrophy. Our objective is to propose a cardiac surveillance and management plan tailored specifically for paediatric patients. We present a family of five members, including two twin sisters with LMNA-related muscular dystrophy. A comprehensive neuromuscular and cardiac work-up was performed in all family members. Genetic analysis using massive sequencing technology was performed in both twins. Clinical assessment showed that only the twins showed diagnoses of LMNA-related muscular dystrophy. Follow-up showed an early onset of symptoms and life-threatening arrhythmias, with differing disease progressions despite both twins passing away. Genetic analysis identified a de novo rare missense deleterious variant in the LMNA gene. Other additional rare variants were identified in genes associated with myasthenic syndrome. Early-onset neuromuscular symptoms could be related to a prognosis of worse life-threatening arrhythmias in LMNA related muscular dystrophy. Being a carrier of other rare variants may be a modifying factor in the progression of the phenotype, although further studies are needed. There is a pressing need for specific cardiac recommendations tailored to the paediatric population to mitigate the risk of malignant arrhythmias.
Asunto(s)
Lamina Tipo A , Distrofias Musculares , Gemelos Monocigóticos , Humanos , Lamina Tipo A/genética , Gemelos Monocigóticos/genética , Femenino , Distrofias Musculares/genética , Distrofias Musculares/terapia , Masculino , Niño , Linaje , Preescolar , Arritmias Cardíacas/genética , Arritmias Cardíacas/etiologíaRESUMEN
Polymerizing laminins are multi-domain basement membrane (BM) glycoproteins that self-assemble into cell-anchored planar lattices to establish the initial BM scaffold. Nidogens, collagen-IV and proteoglycans then bind to the scaffold at different domain loci to create a mature BM. The LN domains of adjacent laminins bind to each other to form a polymer node, while the LG domains attach to cytoskeletal-anchoring integrins and dystroglycan, as well as to sulfatides and heparan sulfates. The polymer node, the repeating unit of the polymer scaffold, is organized into a near-symmetrical triskelion. The structure, recently solved by cryo-electron microscopy in combination with AlphaFold2 modeling and biochemical studies, reveals how the LN surface residues interact with each other and how mutations cause failures of self-assembly in an emerging group of diseases, the LN-lamininopathies, that include LAMA2-related dystrophy and Pierson syndrome.
Asunto(s)
Membrana Basal , Laminina , Humanos , Laminina/metabolismo , Laminina/química , Laminina/genética , Animales , Membrana Basal/metabolismo , Distrofias Musculares/metabolismo , Distrofias Musculares/genética , Deformidades Congénitas de las Extremidades/metabolismo , Deformidades Congénitas de las Extremidades/genética , Mutación , Síndrome Nefrótico , Trastornos de la Pupila , Síndromes Miasténicos CongénitosRESUMEN
Muscular dystrophy is a group of genetic disorders that lead to muscle wasting and loss of muscle function. Identifying genetic modifiers that alleviate symptoms or enhance the severity of a primary disease helps to understand mechanisms behind disease pathology and facilitates discovery of molecular targets for therapy. Several muscular dystrophies are caused by genetic defects in the components of the dystrophin-glycoprotein adhesion complex (DGC). Thrombospondin-4 overexpression has been shown to mitigate dystrophic disease in mouse models for Duchenne muscular dystrophy (dystrophin deficiency) and limb-girdle muscular dystrophy type 2F (LGMD2F, δ-sarcoglycan deficiency), while deletion of the thrombospondin-4 gene exacerbated the diseases. Hence, thrombospondin-4 has been considered a candidate molecule for therapy of muscular dystrophies involving the DGC. We have investigated whether thrombospondin-4 could act as a genetic modifier for other DGC-associated diseases: limb-girdle muscular dystrophy type 2E (LGMD2E, ß-sarcoglycan deficiency) and laminin α2 chain-deficient muscular dystrophy (LAMA2-RD). Deletion of the thrombospondin-4 gene in mouse models for LGMD2E and LAMA2-RD, respectively, did not result in worsening of the dystrophic phenotype. Loss of thrombospondin-4 did not enhance sarcolemma damage and did not impair trafficking of transmembrane receptors integrin α7ß1 and dystroglycan in double knockout muscles. Our results suggest that thrombospondin-4 might not be a relevant therapeutic target for all muscular dystrophies involving the DGC. This data also demonstrates that molecular pathology between very similar diseases like LGMD2E and 2F can differ significantly.
Asunto(s)
Laminina , Ratones Noqueados , Sarcoglicanos , Trombospondinas , Animales , Laminina/metabolismo , Laminina/genética , Laminina/deficiencia , Sarcoglicanos/genética , Sarcoglicanos/deficiencia , Sarcoglicanos/metabolismo , Ratones , Trombospondinas/genética , Trombospondinas/metabolismo , Trombospondinas/deficiencia , Modelos Animales de Enfermedad , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Eliminación de Gen , Distrofias Musculares/genética , Distrofias Musculares/metabolismo , Distrofias Musculares/patología , Distrofia Muscular Animal/genética , Distrofia Muscular Animal/metabolismo , Distrofia Muscular Animal/patologíaRESUMEN
LAMA2-related muscular dystrophy is caused by pathogenic variants of the alpha2 subunit of Laminin. This common form of muscular dystrophy is characterized by elevated CK >1000IU/L, dystrophic changes on muscle biopsy, complete or partial absence of merosin staining, and both central and peripheral nervous system involvement. Advancements in genomic testing using NGS and wider application of RNA sequencing has expanded our knowledge of novel non-coding pathogenic variants in LAMA2. RNA sequencing is an increasingly utilized technique to directly analyze the transcriptome, through creation of a complementary DNA (cDNA) from the transcript within a tissue sample. Here we describe a homozygous deep intronic variant that produces a novel splice junction in LAMA2 identified by RNA sequencing analysis in a patient with a clinical phenotype in keeping with LAMA2-related muscular dystrophy. Furthermore, in this case merosin staining was retained suggestive of a functional deficit.
Asunto(s)
Intrones , Laminina , Distrofias Musculares , Análisis de Secuencia de ARN , Humanos , Laminina/genética , Intrones/genética , Distrofias Musculares/genética , Distrofias Musculares/patología , Distrofias Musculares/diagnóstico , Masculino , Fenotipo , Mutación , FemeninoRESUMEN
LAMA2-related dystrophies (LAMA2-RD) constitute a rare neuromuscular disorder with a broad spectrum of phenotypic severity. Our understanding of the genotype-phenotype correlations in this condition remains incomplete, and reliable clinical data for clinical trial readiness is limited. In this retrospective study, we reviewed the genetic data and medical records of 114 LAMA2-RD patients enrolled at seven research centers in Brazil. We identified 58 different pathogenic variants, including 21 novel ones. Six variants were more prevalent and were present in 81.5% of the patients. Notably, the c.1255del, c.2049_2050del, c.3976 C>T, c.5234+1G>A, and c.4739dup variants were found in patients unable to walk and without cortical malformation. In contrast, the c.2461A>C variant was present in patients who could walk unassisted. Among ambulatory patients, missense variants were more prevalent (p < 0.0001). Although no specific hotspot regions existed in the LAMA2, 51% of point mutations were in the LN domain, and 88% of the missense variants were found within this domain. Functional analysis was performed in one intronic variant (c.4960-17C>A) and revealed an out-of-frame transcript, indicating that the variant creates a cryptic splicing site (AG). Our study has shed light on crucial phenotype-genotype correlations and provided valuable insights, particularly regarding the Latin American population.
Asunto(s)
Estudios de Asociación Genética , Laminina , Humanos , Laminina/genética , Masculino , Brasil/epidemiología , Femenino , Niño , Preescolar , Adolescente , Adulto , Perfil Genético , Fenotipo , Estudios Retrospectivos , Distrofias Musculares/genética , Mutación , Adulto Joven , Predisposición Genética a la Enfermedad , Lactante , Genotipo , Persona de Mediana EdadRESUMEN
Muscular dystrophies (MDs) are inherited genetic diseases causing weakness and degeneration of muscles. The distribution of muscle weakness differs between MDs, involving distal muscles or proximal muscles. While the mutations in most of the MD-associated genes lead to either distal or proximal onset, there are also genes whose mutations can cause both types of onsets. We hypothesized that the genes associated with different MD onsets code proteins with distinct cellular functions. To investigate this, we collected the MD-associated genes and assigned them to three onset groups: genes mutated only in distal onset dystrophies, genes mutated only in proximal onset dystrophies, and genes mutated in both types of onsets. We then systematically evaluated the cellular functions of these gene sets with computational strategies based on functional enrichment analysis and biological network analysis. Our analyses demonstrate that genes mutated in either distal or proximal onset MDs code proteins linked with two distinct sets of cellular processes. Interestingly, these two sets of cellular processes are relevant for the genes that are associated with both onsets. Moreover, the genes associated with both onsets display high centrality and connectivity in the network of muscular dystrophy genes. Our findings support the hypothesis that the proteins associated with distal or proximal onsets have distinct functional characteristics, whereas the proteins associated with both onsets are multifunctional.
Asunto(s)
Debilidad Muscular , Distrofias Musculares , Mutación , Humanos , Distrofias Musculares/genética , Debilidad Muscular/genética , Redes Reguladoras de Genes , Biología Computacional/métodos , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiopatología , Músculo Esquelético/patologíaRESUMEN
INTRODUCTION/AIMS: Early diagnosis of a chronic neuromuscular disease such as muscular dystrophy (MD) generally excludes an individual from active-duty military service. However, it is not known whether veterans are sometimes diagnosed with milder forms of MD at a later timepoint. We aimed to determine the prevalence of MD in a veterans health system. METHODS: We abstracted clinical and genetic test data on patients who received care for a diagnosis of MD at the North Florida/South Georgia Veterans Health System between 2008 and 2021. We then determined which of these individuals would meet criteria for a definite diagnosis of MD, based on electrodiagnostic testing, muscle biopsy, and genetic testing of the individual or an affected first degree relative. RESULTS: We identified 12 patients with definite MD and 36 with possible or probable MD. The definite cases included myotonic dystrophy type 1 (4), myotonic dystrophy type 2 (3), oculopharyngeal MD (2), Becker MD (1), distal MD (1), and facioscapulohumeral MD (1). At least five of the cases classified as definite developed symptoms after discharge from active duty. DISCUSSION: Clinicians who care for veterans should be knowledgeable about, and have access to, diagnostic testing and treatment options for MD. When conducting MD surveillance, it is important to include veterans health systems as a data source. Mild cases of MD and those of later onset appear to be compatible in some cases with successful completion of military service.
Asunto(s)
Distrofias Musculares , Veteranos , Humanos , Masculino , Persona de Mediana Edad , Femenino , Adulto , Distrofias Musculares/diagnóstico , Distrofias Musculares/epidemiología , Distrofias Musculares/genética , Anciano , Salud de los Veteranos , PrevalenciaRESUMEN
Phosphatidylcholine (PC) is the major membrane phospholipid in most eukaryotic cells. Bi-allelic loss of function variants in CHKB, encoding the first step in the synthesis of PC, is the cause of a rostrocaudal muscular dystrophy in both humans and mice. Loss of sarcolemma integrity is a hallmark of muscular dystrophies; however, how this occurs in the absence of choline kinase function is not known. We determine that in Chkb -/- mice there is a failure of the α7ß1 integrin complex that is specific to affected muscle. We observed that in Chkb -/- hindlimb muscles there is a decrease in sarcolemma association/abundance of the PI(4,5)P2 binding integrin complex proteins vinculin, and α-actinin, and a decrease in actin association with the sarcolemma. In cells, pharmacological inhibition of choline kinase activity results in internalization of a fluorescent PI(4,5)P2 reporter from discrete plasma membrane clusters at the cell surface membrane to cytosol, this corresponds with a decreased vinculin localization at plasma membrane focal adhesions that was rescued by overexpression of CHKB.
Asunto(s)
Colina Quinasa , Integrinas , Ratones Noqueados , Distrofias Musculares , Sarcolema , Vinculina , Animales , Ratones , Vinculina/metabolismo , Vinculina/genética , Distrofias Musculares/metabolismo , Distrofias Musculares/genética , Integrinas/metabolismo , Colina Quinasa/metabolismo , Colina Quinasa/genética , Sarcolema/metabolismo , Humanos , Adhesiones Focales/metabolismo , Membrana Celular/metabolismo , Actinina/metabolismo , Actinina/genética , Músculo Esquelético/metabolismo , Fosfatidilinositol 4,5-Difosfato/metabolismo , Actinas/metabolismo , Modelos Animales de EnfermedadRESUMEN
Desminopathy R350P is a human myopathy that is characterized by the progressive loss of muscle fiber organization. This results in the loss of muscle size, mobility, and strength. In desminopathy, inflammation affects muscle homeostasis and repair, and contributes to progressive muscle deterioration. Mitochondria morphology was also suggested to affect desminopathy progression. Epicatechin (Epi)-a natural compound found in cacao-has been proposed to regulate inflammatory signaling and mitochondria morphology in human and animal models. Hence, we hypothesize chronic Epi consumption to improve inflammatory pathway and mitochondria morphology in the peripheral blood mononuclear cells (PBMCs) of a desminopathy R350P patient. We found that 12 weeks of Epi consumption partially restored TRL4 signaling, indicative of inflammatory signaling and mitochondria morphology in the desminopathy patient. Moreover, Epi consumption improved blood health parameters, including reduced HOMA-IR and IL-6 levels in the desminopathy patient. This indicates that Epi consumption could be a useful tool to slow disease progression in desminopathy patients.
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Catequina , Leucocitos Mononucleares , Mitocondrias , Humanos , Catequina/farmacología , Catequina/administración & dosificación , Leucocitos Mononucleares/metabolismo , Leucocitos Mononucleares/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Mitocondrias/patología , Masculino , Distrofias Musculares/metabolismo , Distrofias Musculares/patología , Distrofias Musculares/tratamiento farmacológico , Distrofias Musculares/genética , Adulto , Femenino , Inflamación/metabolismo , Inflamación/patología , Cardiomiopatías/metabolismo , Cardiomiopatías/patología , Cardiomiopatías/tratamiento farmacológico , Desmina/metabolismo , Desmina/genéticaRESUMEN
Extracellular matrix (ECM) pathologic remodeling underlies many disorders, including muscular dystrophy. Tissue decellularization removes cellular components while leaving behind ECM components. We generated "on-slide" decellularized tissue slices from genetically distinct dystrophic mouse models. The ECM of dystrophin- and sarcoglycan-deficient muscles had marked thrombospondin 4 deposition, while dysferlin-deficient muscle had excess decorin. Annexins A2 and A6 were present on all dystrophic decellularized ECMs, but annexin matrix deposition was excessive in dysferlin-deficient muscular dystrophy. Muscle-directed viral expression of annexin A6 resulted in annexin A6 in the ECM. C2C12 myoblasts seeded onto decellularized matrices displayed differential myoblast mobility and fusion. Dystrophin-deficient decellularized matrices inhibited myoblast mobility, while dysferlin-deficient decellularized matrices enhanced myoblast movement and differentiation. Myoblasts treated with recombinant annexin A6 increased mobility and fusion like that seen on dysferlin-deficient decellularized matrix and demonstrated upregulation of ECM and muscle cell differentiation genes. These findings demonstrate specific fibrotic signatures elicit effects on myoblast activity.
Asunto(s)
Diferenciación Celular , Movimiento Celular , Disferlina , Matriz Extracelular , Mioblastos , Sarcoglicanos , Animales , Mioblastos/metabolismo , Mioblastos/citología , Matriz Extracelular/metabolismo , Ratones , Sarcoglicanos/genética , Sarcoglicanos/metabolismo , Disferlina/genética , Disferlina/metabolismo , Distrofias Musculares/genética , Distrofias Musculares/metabolismo , Distrofias Musculares/patología , Distrofina/genética , Distrofina/metabolismo , Anexina A2/genética , Anexina A2/metabolismo , Decorina/genética , Decorina/metabolismo , Línea Celular , Modelos Animales de Enfermedad , Músculo Esquelético/metabolismoRESUMEN
Dysferlinopathies refer to a spectrum of muscular dystrophies that cause progressive muscle weakness and degeneration. They are caused by mutations in the DYSF gene, which encodes the dysferlin protein that is crucial for repairing muscle membranes. This review delves into the clinical spectra of dysferlinopathies, their molecular mechanisms, and the spectrum of emerging therapeutic strategies. We examine the phenotypic heterogeneity of dysferlinopathies, highlighting the incomplete understanding of genotype-phenotype correlations and discussing the implications of various DYSF mutations. In addition, we explore the potential of symptomatic, pharmacological, molecular, and genetic therapies in mitigating the disease's progression. We also consider the roles of diet and metabolism in managing dysferlinopathies, as well as the impact of clinical trials on treatment paradigms. Furthermore, we examine the utility of animal models in elucidating disease mechanisms. By culminating the complexities inherent in dysferlinopathies, this write up emphasizes the need for multidisciplinary approaches, precision medicine, and extensive collaboration in research and clinical trial design to advance our understanding and treatment of these challenging disorders.
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Distrofia Muscular de Cinturas , Distrofias Musculares , Animales , Proteínas Musculares/genética , Proteínas de la Membrana/genética , Distrofia Muscular de Cinturas/genética , Distrofia Muscular de Cinturas/terapia , Distrofia Muscular de Cinturas/metabolismo , Distrofias Musculares/genética , MutaciónRESUMEN
We describe the case of a 19-month-old girl presenting with gross motor delays, hypotonia, diminished deep tendon reflexes, hyperCKaemia, extensive white matter changes on MRI brain, and electromyography studies consistent with myopathy. The differential diagnosis for infantile-onset hypotonia and muscle weakness is broad. It includes numerous subtypes of genetic disorders, including congenital muscular dystrophies, congenital myopathies, congenital myasthenic syndromes, spinal muscular atrophy, single-gene genetic syndromes, and inborn errors of metabolism. We outline our clinical approach leading to the diagnosis of a distinctive genetic neuromuscular condition essential for neurologists and geneticists working with patients of all ages to recognize.
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Enfermedades Musculares , Distrofias Musculares , Sustancia Blanca , Femenino , Humanos , Lactante , Hipotonía Muscular/etiología , Sustancia Blanca/diagnóstico por imagen , Enfermedades Musculares/genética , Distrofias Musculares/genética , Razonamiento ClínicoRESUMEN
LMNA-related congenital muscular dystrophy (L-CMD) is caused by mutations in the LMNA gene, encoding lamin A/C. To further understand the molecular mechanisms of L-CMD, proteomic profiling using DIA mass spectrometry was conducted on immortalized myoblasts and myotubes from controls and L-CMD donors each harbouring a different LMNA mutation (R249W, del.32 K and L380S). Compared to controls, 124 and 228 differentially abundant proteins were detected in L-CMD myoblasts and myotubes, respectively, and were associated with enriched canonical pathways including synaptogenesis and necroptosis in myoblasts, and Huntington's disease and insulin secretion in myotubes. Abnormal nuclear morphology and reduced lamin A/C and emerin abundance was evident in all L-CMD cell lines compared to controls, while nucleoplasmic aggregation of lamin A/C was restricted to del.32 K cells, and mislocalization of emerin was restricted to R249W cells. Abnormal nuclear morphology indicates loss of nuclear lamina integrity as a common feature of L-CMD, likely rendering muscle cells vulnerable to mechanically induced stress, while differences between L-CMD cell lines in emerin and lamin A localization suggests that some molecular alterations in L-CMD are mutation specific. Nonetheless, identifying common proteomic alterations and molecular pathways across all three L-CMD lines has highlighted potential targets for the development of non-mutation specific therapies.
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Lamina Tipo A , Distrofias Musculares , Proteómica , Humanos , Lamina Tipo A/genética , Lamina Tipo A/metabolismo , Distrofias Musculares/genética , Distrofias Musculares/metabolismo , Distrofias Musculares/patología , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patología , Mutación , Mioblastos/metabolismo , Masculino , Línea Celular , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismoRESUMEN
LMNA gene mutation can cause muscular dystrophy, and post-translational modification plays a critical role in regulating its function. Here, we identify that lamin A is palmitoylated at cysteine 522, 588, and 591 residues, which are reversely catalyzed by palmitoyltransferase zinc finger DHHC-type palmitoyltransferase 5 (ZDHHC5) and depalmitoylase α/ß hydrolase domain 7 (ABHD7). Furthermore, the metabolite lactate promotes palmitoylation of lamin A by inhibiting the interaction between it and ABHD7. Interestingly, low-level palmitoylation of lamin A promotes, whereas high-level palmitoylation of lamin A inhibits, murine myoblast differentiation. Together, these observations suggest that ABHD7-mediated depalmitoylation of lamin A controls myoblast differentiation.
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Lamina Tipo A , Distrofias Musculares , Animales , Ratones , Diferenciación Celular , Lamina Tipo A/metabolismo , Distrofias Musculares/genética , Mioblastos/metabolismo , Procesamiento Proteico-PostraduccionalRESUMEN
Lamins are inner nuclear membrane proteins that belong to the intermediate filament family. Lamin A/C lie adjacent to the heterochromatin structure in polymer form, providing skeletal to the nucleus. Based on the localization, lamin A/C provides nuclear stability and cytoskeleton to the nucleus and modulates chromatin organization and gene expression. Besides being the structural protein making the inner nuclear membrane in polymer form, lamin A/C functions as a signalling molecule involved in gene expression as an enhancer inside the nucleus. Lamin A/C regulates various cellular pathways like autophagy and energy balance in the cytoplasm. Its expression is highly variable in differentiated tissues, higher in hard tissues like bone and muscle cells, and lower in soft tissues like the liver and brain. In muscle cells, including the heart, lamin A/C must be expressed in a balanced state. Lamin A/C mutation is linked with various diseases, such as muscular dystrophy, lipodystrophy, and cardiomyopathies. It has been observed that a good number of mutations in the LMNA gene impact cardiac activity and its function. Although several works have been published, there are still several unexplored areas left regarding the lamin A/C function and structure in the cardiovascular system and its pathological state. In this review, we focus on the structural organization, expression pattern, and function of lamin A/C, its interacting partners, and the pathophysiology associated with mutations in the lamin A/C gene, with special emphasis on cardiovascular diseases. With the recent finding on lamin A/C, we have summarized the possible therapeutic interventions to treat cardiovascular symptoms and reverse the molecular changes.
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Cardiomiopatías , Distrofias Musculares , Humanos , Lamina Tipo A/genética , Lamina Tipo A/química , Lamina Tipo A/metabolismo , Cardiomiopatías/genética , Cardiomiopatías/terapia , Distrofias Musculares/genética , Distrofias Musculares/patología , Mutación , PolímerosRESUMEN
SNURPORTIN-1, encoded by SNUPN, plays a central role in the nuclear import of spliceosomal small nuclear ribonucleoproteins. However, its physiological function remains unexplored. In this study, we investigate 18 children from 15 unrelated families who present with atypical muscular dystrophy and neurological defects. Nine hypomorphic SNUPN biallelic variants, predominantly clustered in the last coding exon, are ascertained to segregate with the disease. We demonstrate that mutant SPN1 failed to oligomerize leading to cytoplasmic aggregation in patients' primary fibroblasts and CRISPR/Cas9-mediated mutant cell lines. Additionally, mutant nuclei exhibit defective spliceosomal maturation and breakdown of Cajal bodies. Transcriptome analyses reveal splicing and mRNA expression dysregulation, particularly in sarcolemmal components, causing disruption of cytoskeletal organization in mutant cells and patient muscle tissues. Our findings establish SNUPN deficiency as the genetic etiology of a previously unrecognized subtype of muscular dystrophy and provide robust evidence of the role of SPN1 for muscle homeostasis.