Clinical utility of RNA sequencing to resolve unusual GNE myopathy with a novel promoter deletion.
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ABSTRACT:
SUBMITTER: Chakravorty S
PROVIDER: S-EPMC7688010 | biostudies-literature | 2019 Jul
REPOSITORIES: biostudies-literature
Publications
Clinical utility of RNA sequencing to resolve unusual GNE myopathy with a novel promoter deletion.
Chakravorty Samya S Berger Kiera K Arafat Dalia D Nallamilli Babi Ramesh Reddy BRR Subramanian Hari Prasanna HP Joseph Soumya S Anderson Mary E ME Campbell Kevin P KP Glass Jonathan J Gibson Greg G Hegde Madhuri M
Muscle & nerve 20190429 1
<h4>Introduction</h4>UDP N-acetylglucosamine2-epimerase/N-acetylmannosamine-kinase (GNE) gene mutations can cause mostly autosomal-recessive myopathy with juvenile-onset known as hereditary inclusion-body myopathy (HIBM).<h4>Methods</h4>We describe a family of a patient showing an unusual HIBM with both vacuolar myopathy and myositis without quadriceps-sparing, hindering diagnosis. We show how genetic testing with functional assays, clinical transcriptome sequencing (RNA-seq) in particular, help ...[more]
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Project description:GNE myopathy is a rare genetic disease characterized by progressive muscle atrophy and weakness. It is caused by biallelic mutations in the GNE gene that encodes for the bifunctional enzyme, uridine diphosphate (UDP)-N-acetylglucosamine (GlcNAc) 2-epimerase/N-acetylmannosamine (ManNAc) kinase. Typical characteristics of GNE myopathy include progressive myopathy, first involving anterior tibialis muscle and sparing the quadriceps, and rimmed vacuoles on muscle biopsy. Identifying biallelic mutations by sequencing of the GNE gene confirms the diagnosis of GNE myopathy. In a subset of patients, diagnostic confirmation is challenged by the identification of mutations in only one allele, suggesting mutations in deep intronic regions or regulatory regions.We performed targeted sequencing and copy number variant (CNV) analysis of GNE in two siblings who clinically presented with GNE myopathy. Further molecular and biochemical studies were done to characterize the effect of a previously uncharacterized GNE mutation.We report two siblings of Indian descent with characteristic features of GNE myopathy, including progressive skeletal muscle weakness initially involving the anterior tibialis, and rimmed vacuoles on muscle biopsy, in which a heterozygous mutation, p.Val727Met, was identified in both affected siblings, but no other deleterious variants in either coding region or exon-intron boundaries of the gene. Subsequent insertion/deletion analysis identified a novel 11.3-kb deletion (Chr9 [GRCh37]: g.36257583_36268910del) encompassing the GNE promoter region, with breakpoints residing in Alu repeats. Gene expression analysis revealed reduced GNE mRNA and protein levels, confirming decreased expression of the deleted allele harboring the deletion.We have identified GNE as one of the genes susceptible to Alu-mediated recombination. Our findings suggest that the deletion may encompass the promoter or another region necessary for GNE expression. In patients with typical manifestations of GNE myopathy and a single GNE variant identified, copy number variant (CNV) analysis may be useful in arriving at the diagnosis.
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Project description:GNE myopathy (GNEM) is a rare hereditary disease, but at the same time, it is the most common distal myopathy in several countries due to a founder effect of some pathogenic variants in the GNE gene. We collected the largest cohort of patients with GNEM from Russia and analyzed their mutational spectrum and clinical data. In our cohort, 10 novel variants were found, including 2 frameshift variants and 2 large deletions. One novel missense variant c.169_170delGCinsTT (p.(Ala57Phe)) was detected in 4 families in a homozygous state and in 3 unrelated patients in a compound heterozygous state. It was the second most frequent variant in our cohort. All families with this novel frequent variant were non-consanguineous and originated from the 3 neighboring areas in the European part of Russia. The clinical picture of the patients carrying this novel variant was typical, but the severity of clinical manifestation differed significantly. In our study, we reported two atypical cases expanding the phenotypic spectrum of GNEM. One female patient had severe quadriceps atrophy, hand joint contractures, keloid scars, and non-classical pattern on leg muscle magnetic resonance imaging, which was more similar to atypical collagenopathy rather than GNEM. Another patient initially had been observed with spinal muscular atrophy due to asymmetric atrophy of hand muscles and results of electromyography. The peculiar pattern of muscle involvement on magnetic resonance imaging consisted of pronounced changes in the posterior thigh muscle group with relatively spared muscles of the lower legs, apart from the soleus muscles. Different variants in the GNE gene were found in both atypical cases. Thus, our data expand the mutational and clinical spectrum of GNEM.
| S-EPMC9690815 | biostudies-literature
Project description:The GNE gene encodes the rate-limiting, bifunctional enzyme of sialic acid biosynthesis, uridine diphosphate-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE). Biallelic GNE mutations underlie GNE myopathy, an adult-onset progressive myopathy. GNE myopathy-associated GNE mutations are predominantly missense, resulting in reduced, but not absent, GNE enzyme activities. The exact pathomechanism of GNE myopathy remains unknown, but likely involves aberrant (muscle) sialylation. Here, we summarize 154 reported and novel GNE variants associated with GNE myopathy, including 122 missense, 11 nonsense, 14 insertion/deletions, and seven intronic variants. All variants were deposited in the online GNE variation database (http://www.dmd.nl/nmdb2/home.php?select_db=GNE). We report the predicted effects on protein function of all variants well as the predicted effects on epimerase and/or kinase enzymatic activities of selected variants. By analyzing exome sequence databases, we identified three frequently occurring, unreported GNE missense variants/polymorphisms, important for future sequence interpretations. Based on allele frequencies, we estimate the world-wide prevalence of GNE myopathy to be ?4-21/1,000,000. This previously unrecognized high prevalence confirms suspicions that many patients may escape diagnosis. Awareness among physicians for GNE myopathy is essential for the identification of new patients, which is required for better understanding of the disorder's pathomechanism and for the success of ongoing treatment trials.
| S-EPMC4172345 | biostudies-literature
Project description:BackgroundGNE myopathy is a rare distal myopathy caused by mutations of the GNE gene. A few cases of GNE myopathy accompanied by neurogenic features of electrophysiology mimicking hereditary motor neuropathy were reported recently. We confirmed this feature and described the clinical phenotype and mutations of GNE myopathy in these rare cases.ResultsThe absence of lower limb tendon reflexes, decreased compound muscle action potentials in lower leg motor nerves, and neurogenic pattern of electromyography suggested neuropathy in four patients. However, muscle pathology revealed a predominantly myogenic pattern. The follow-up electroneurography results implied that the compound motor action potential amplitudes deteriorated over time. Next-generation sequencing identified three novel variants of the GNE gene, c.2054T > C (p.Val685Ala), c.424G > A (p.Gly142Arg) and c.944T > C (p.Phe315Ser), as well as two hotspot mutations, c.115C > T(p.Arg39*) and c.620A > T(p.Asp207Val), in these patients. These novel mutations cosegregated with disease in the family.ConclusionsThese rare cases supported the existence of neurogenic features of electrophysiology different from the typical myopathic pattern of GNE myopathy.
| S-EPMC9118620 | biostudies-literature
Project description:GNE myopathy is an autosomal recessive muscle disease caused by biallelic mutations in GNE, a gene encoding for a single protein with key enzymatic activities, UDP-N-acetylglucosamine 2-epimerase and N-acetylmannosamine kinase, in sialic acid biosynthetic pathway. The diagnosis should be considered primarily in patients presenting with distal weakness (foot drop) in early adulthood (other onset symptoms are possible too). The disease slowly progresses to involve other lower and upper extremities' muscles, with marked sparing of the quadriceps. Characteristic findings on biopsies of affected muscles include 'rimmed' (autophagic) vacuoles, aggregation of various proteins and fibre size variation. The diagnosis is confirmed by sequencing of the GNE gene. Note that we use a new mutation nomenclature based on the longest transcript (GenBank: NM_001128227), which encodes a 31-amino acid longer protein than the originally described one (GenBank: NM_005476), which has been used previously in most papers. Based upon the pathophysiology of the disease, recent clinical trials as well as early gene therapy trials have evaluated the use of sialic acid or N-acetylmannosamine (a precursor of sialic acid) in patients with GNE myopathy. Now that therapies are under investigation, it is critical that a timely and accurate diagnosis is made in patients with GNE myopathy.
| S-EPMC4394625 | biostudies-literature
Project description:GNE myopathy, previously known as hereditary inclusion body myopathy (HIBM), or Nonaka myopathy, is a rare autosomal recessive muscle disease characterized by progressive skeletal muscle atrophy. It has an estimated prevalence of 1 to 9:1,000,000. GNE myopathy is caused by mutations in the GNE gene which encodes the rate-limiting enzyme of sialic acid biosynthesis. The pathophysiology of the disease is not entirely understood, but hyposialylation of muscle glycans is thought to play an essential role. The typical presentation is bilateral foot drop caused by weakness of the anterior tibialis muscles with onset in early adulthood. The disease slowly progresses over the next decades to involve skeletal muscles throughout the body, with relative sparing of the quadriceps until late stages of the disease. The diagnosis of GNE myopathy should be considered in young adults presenting with bilateral foot drop. Histopathologic findings on muscle biopsies include fiber size variation, atrophic fibers, lack of inflammation, and the characteristic "rimmed" vacuoles on modified Gomori trichome staining. The diagnosis is confirmed by the presence of pathogenic (mostly missense) mutations in both alleles of the GNE gene. Although there is no approved therapy for this disease, preclinical and clinical studies of several potential therapies are underway, including substrate replacement and gene therapy-based strategies. However, developing therapies for GNE myopathy is complicated by several factors, including the rare incidence of disease, limited preclinical models, lack of reliable biomarkers, and slow disease progression.
| S-EPMC6277305 | biostudies-literature
Project description:GNE myopathy is a slowly progressive autosomal recessive myopathy caused by mutations in the GNE (glucosamine (UDP-N-acetyl)-2-epimerase/N-acetylmannosamine kinase) gene. This study aimed to (1) develop a nationwide patient registry for GNE myopathy in order to facilitate the planning of clinical trials and recruitment of candidates, and (2) gain further insight into the disease for the purpose of improving therapy and care.Medical records of genetically-confirmed patients with GNE myopathy at the National Center Hospital of the National Center of Neurology and Psychiatry (NCNP) were retrospectively reviewed in order to obtain data reflecting the severity and progression of the disease. We also referred to items in the datasheet of the nationwide registry of dystrophinopathy patients in the Registry of Muscular Dystrophies (Remudy). Items selected for the registration sheet included age, sex, age at onset, past history and complications, family history, body weight and height, pathological findings of muscle biopsy, grip power, walking ability, respiratory function, cardiac function, willingness to join upcoming clinical trials, and participation in patient associations. A copy of the original genetic analysis report was required of each patient.We successfully established the Remudy-GNE myopathy. Currently, 121 patients are registered nationwide, and 93 physicians from 73 hospitals collaborated to establish the registry. The mean age at onset was 27.7?±?9.6 years, and 19.8% (24/121) of patients could walk without assistance. Mean presumed durations from onset to use of assistive devices (cane and/or braces) and a wheelchair, and loss of ambulation were 12.4, 15.2, and 21.1 years, respectively. Three patients had a past history and/or complication of idiopathic thrombocytopenia. To share the progress of this study with the community, newsletters were published on a regular basis, and included information regarding new phase I clinical trials for GNE myopathy. The newsletters also served as a medium to bring attention to the importance of respiratory evaluation and care for respiratory insufficiency.The Japanese Remudy-GNE myopathy is useful for clarifying the natural history of the disease and recruiting patients with genetically-confirmed GNE myopathy for clinical trials.
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Project description:BACKGROUND:UDP-GlcNAc 2-epimerase/ManNAc 6-kinase (GNE) is a bifunctional enzyme responsible for the first committed steps in the synthesis of sialic acid, a common terminal monosaccharide in both protein and lipid glycosylation. GNE mutations are responsible for a rare autosomal recessive neuromuscular disorder, GNE myopathy (also called hereditary inclusion body myopathy). The connection between the impairment of sialic acid synthesis and muscle pathology in GNE myopathy remains poorly understood. METHODS:Glycosphingolipid (GSL) analysis was performed by HPLC in multiple models of GNE myopathy, including patients' fibroblasts and plasma, control fibroblasts with inhibited GNE epimerase activity through a novel imino sugar, and tissues of Gne(M712T/M712T) knock-in mice. RESULTS:Not only neutral GSLs, but also sialylated GSLs, were significantly increased compared to controls in all tested models of GNE myopathy. Treatment of GNE myopathy fibroblasts with N-acetylmannosamine (ManNAc), a sialic acid precursor downstream of GNE epimerase activity, ameliorated the increased total GSL concentrations. CONCLUSION:GNE myopathy models have increased total GSL concentrations. ManNAc supplementation results in decrease of GSL levels, linking abnormal increase of total GSLs in GNE myopathy to defects in the sialic acid biosynthetic pathway. These data advocate for further exploring GSL concentrations as an informative biomarker, not only for GNE myopathy, but also for other disorders of sialic acid metabolism.
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Project description:ObjectiveTo characterize muscle involvement and evaluate disease severity in patients with GNE myopathy using skeletal muscle MRI and proton magnetic resonance spectroscopy (1H-MRS).MethodsSkeletal muscle imaging of the lower extremities was performed in 31 patients with genetically confirmed GNE myopathy, including T1-weighted and short tau inversion recovery (STIR) images, T1 and T2 mapping, and 1H-MRS. Measures evaluated included longitudinal relaxation time (T1), transverse relaxation time (T2), and 1H-MRS fat fraction (FF). Thigh muscle volume was correlated with relevant measures of strength, function, and patient-reported outcomes.ResultsThe cohort was representative of a wide range of disease progression. Contractile thigh muscle volume ranged from 5.51% to 62.95% and correlated with thigh strength (r = 0.91), the 6-minute walk test (r = 0.82), the adult myopathy assessment tool (r = 0.83), the activities-specific balance confidence scale (r = 0.65), and the inclusion body myositis functional rating scale (r = 0.62). Four stages of muscle involvement were distinguished by qualitative (T1W and STIR images) and quantitative methods: stage I: unaffected muscle (T1 = 1,033 ± 74.2 ms, T2 = 40.0 ± 1.9 ms, FF = 7.4 ± 3.5%); stage II: STIR hyperintense muscle with minimal or no fat infiltration (T1 = 1,305 ± 147 ms, T2 = 50.2 ± 3.5 ms, FF = 27.6 ± 12.7%); stage III: fat infiltration and STIR hyperintensity (T1 = 1,209 ± 348 ms, T2 = 73.3 ± 12.6 ms, FF = 57.5 ± 10.6%); and stage IV: complete fat replacement (T1 = 318 ± 39.9 ms, T2 = 114 ± 21.2 ms, FF = 85.6 ± 4.2%). 1H-MRS showed a significant decrease in intramyocellular lipid and trimethylamines between stage I and II, suggesting altered muscle metabolism at early stages.ConclusionMRI biomarkers can monitor muscle involvement and determine disease severity noninvasively in patients with GNE myopathy.Clinicaltrialsgov identifierNCT01417533.
| S-EPMC7884988 | biostudies-literature
Project description:GNE myopathy is a rare, recessively inherited, early adult-onset myopathy, characterized by distal and proximal muscle degeneration which often spares the quadriceps. It is caused by mutations in the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase gene (GNE). This study aimed to identify the disease-causing mutation in a three-generation Han-Chinese family with members who have been diagnosed with myopathy. A homozygous missense mutation, c.1627G>A (p.V543M) in the GNE gene co-segregates with the myopathy present in this family. A GNE myopathy diagnosis is evidenced by characteristic clinical manifestations, rimmed vacuoles in muscle biopsies and the presence of biallelic GNE mutations. This finding broadens the GNE gene mutation spectrum and extends the GNE myopathy phenotype spectrum.
| S-EPMC6201217 | biostudies-other