Nonketotic hyperglycinemia: Functional assessment of missense variants in<i>GLDC</i>to understand phenotypes of the disease

Bravo-Alonso, Irene; Navarrete, Rosa; Arribas-Carreira, Laura; Perona, Almudena; Abia, David; Couce, María L.; García‐Cazorla, Àngels; Morais, Ana Carolina Nunes de; Domingo, Rosario; Ramos, María Antonia; Swanson, Michael A.; Hove, Johan L.K. Van; Ugarte, Magdalena; Pérez, Belén; Pérez‐Cerdá, Celia; Rodríguez‐Pombo, Pilar

doi:10.1002/humu.23208

Cited by 14 publications

(16 citation statements)

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“…Potential 3’ and 5’ splice sites were analysed as previously described [24] using the default settings of Alamut ® Visual Interactive Bio v2.7.1 software. Those variants prioritized to be causal of CLA were confirmed by conventional Sanger sequencing using the BigDye Terminator Cycle Sequencing Kit (Applied Biosystems, Foster City, CA, USA), using both patient genomic DNA and that of the progenitors if available.…”

Section: Methodsmentioning

confidence: 99%

Genes and Variants Underlying Human Congenital Lactic Acidosis—From Genetics to Personalized Treatment

Bravo-Alonso

Navarrete

Vega

et al. 2019

JCM

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Congenital lactic acidosis (CLA) is a rare condition in most instances due to a range of inborn errors of metabolism that result in defective mitochondrial function. Even though the implementation of next generation sequencing has been rapid, the diagnosis rate for this highly heterogeneous allelic condition remains low. The present work reports our group’s experience of using a clinical/biochemical analysis system in conjunction with genetic findings that facilitates the taking of timely clinical decisions with minimum need for invasive procedures. The system’s workflow combines different metabolomics datasets and phenotypic information with the results of clinical exome sequencing and/or RNA analysis. The system’s use detected genetic variants in 64% of a cohort of 39 CLA-patients; these variants, 14 of which were novel, were found in 19 different nuclear and two mitochondrial genes. For patients with variants of unknown significance, the genetic analysis was combined with functional genetic and/or bioenergetics analyses in an attempt to detect pathogenicity. Our results warranted subsequent testing of antisense therapy to rescue the abnormal splicing in cultures of fibroblasts from a patient with a defective GFM1 gene. The discussed system facilitates the diagnosis of CLA by avoiding the need to use invasive techniques and increase our knowledge of the causes of this condition.

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Section: Methodsmentioning

confidence: 99%

Genes and Variants Underlying Human Congenital Lactic Acidosis—From Genetics to Personalized Treatment

Bravo-Alonso

Navarrete

Vega

et al. 2019

JCM

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“…xii. Residue is at the known dimerization interface (because dimerization may be 522 genotype was known and the patient had at least one missense mutation [13,14,29,[46][47][48][49][50][51][52][53][54][55][56]. A 540 comprehensive list of NKH symptoms in the clinical data was created ( Table 2), and we developed 541 a clinical outcome scoring scale based on the four major symptomatic domains of 1) seizures, 2) 542 cognitive disorders, 3) muscle/movement control and 4) brain malformations ( Table 3).…”

Section: Conservation Of Amino Acid Substitution (Based On Blosum62 Mmentioning

confidence: 99%

“…Of the remaining 255, only 49 mutations have been 84 assessed for loss of enzymatic activity compared to the wild type. Of these, only 9 have been 85 5 analyzed for their potential effect on GLDC-protein structure based on in silico 3D-modeling [14]. 86Together, the findings summarized in Fig 1A-C show the overall lack of annotation for NKH 87 mutations and demonstrate the need for improved tools and analyses to better understand 88 mutations across the gene, how they may cause deficiency in the encoded protein and thereby 89 impact disease severity.…”

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Large scale analyses of genotype-phenotype relationships of glycine decarboxylase mutations and neurological disease severity

Farris

Calhoun

Alam

et al. 2019

Preprint

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16Monogenetic diseases provide unique opportunity for studying complex, clinical states that 17 underlie neurological severity. Loss of glycine decarboxylase (GLDC) can severely impact 18 neurological development as seen in non-ketotic hyperglycinemia (NKH). NKH is a neuro-19 metabolic disorder lacking quantitative predictors of disease states. It is characterized by 20 elevation of glycine, seizures and failure to thrive, but glycine reduction often fails to confer 21 neurological benefit, suggesting need for alternate tools to distinguish severe from attenuated 22 disease. A major challenge has been that there are 255 unique disease-causing missense 23 mutations in GLDC, of which 206 remain entirely uncharacterized. Here we report a 24Multiparametric Mutation Score (MMS) developed by combining in silico predictions of stability, 25 evolutionary conservation and protein interaction models and suitable to assess 251 of 255 26 mutations. In addition, we created a quantitative scale of clinical disease severity comprising of 27 four major disease domains (seizure, cognitive failure, muscular and motor control and brain-28 malformation) to comprehensively score patient symptoms identified in 131 clinical reports 29 published over the last 15 years. The resulting patient Clinical Outcomes Scores (COS) were 30 used to optimize the MMS for biological and clinical relevance and yield a patient Weighted 31Multiparametric Mutation Score (WMMS) that separates severe from attenuated neurological 32 disease (p < 3.5e-5). Our study provides understanding for developing quantitative tools to predict 33 clinical severity of neurological disease and a clinical scale that advances monitoring disease 34 progression needed to evaluate new treatments for NKH. 35 lack of mutation-based predictors of disease progression and a quantitative scale of disease 61 severity scale impedes both management of NKH as well as development of therapies to treat 62 and cure the disease. 63 64In this study, we developed a multi-parametric mutation scale applicable to all but 4 of 255 65 missense NKH mutations across the GLDC gene and thereby assigned a multi-parametric 66 mutation score (MMS) to 251 patient mutations. The MMS was further optimized against a newly 67 developed patient-based clinical outcomes score that was based on major symptomatic domains 68 extracted from a comprehensive review of clinical cases reported in the literature. Our findings 69 yield a quantitative tool with high predictive value to support disease management and emerging 70 treatments associated with >95% of known clinical NKH mutations. 71 72 Results 73Positional distribution of NKH Missense Mutations. 74The most recently published comprehensive list of NKH missense mutations lists 171 unique 75 mutations across the length of GLDC [8]. To this, we added 85 missense mutations based on 76 additional literature and the Clinvar database. This yielded a list of 256 mutations ascribed to 213 77 unique residues (Table S1, Fig 1A). NKH missense mutations were found in the C-te...

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“…The GCS consists of the enzymes glycine decarboxylase (P-protein), amino-methyltransferase (T-protein), hydrogen carrier protein (H-protein), and dihydrolipoamide dehydrogenase (L-protein) [ 5 ]. The P, T, and H proteins are encoded by GLDC (OMIM 238300), AMT (OMIM 238310), and GCSH (OMIM 238330) genes, respectively.…”

Section: Introductionmentioning

confidence: 99%

A novel compound heterozygous variant identified in GLDC gene in a Chinese family with non-ketotic hyperglycinemia

Lin¹,

Zheng²,

Sun

et al. 2018

BMC Med Genet

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BackgroundNon-ketotic hyperglycinemia (NKH) is a rare, devastating autosomal recessive disorder of glycine metabolism with a very poor prognosis. Currently, few studies have reported genetic profiling of Chinese NKH patients. This study aimed to identify the genetic mutations in a Chinese family with NKH.MethodsA Chinese family of Han ethnicity, with three siblings with NKH was studied. Sanger sequencing and multiplex ligation-dependent probe amplification combined with SYBR green real-time quantitative PCR was used to identify potential mutations in the GLDC, AMT and GCSH genes. The potential pathogenicity of the identified missense mutation was analyzed using SIFT, PolyPhen-2, PROVEAN and MutationTaster software.ResultsAll patients exhibited severe and progressive clinical symptoms, including lethargy, hypotonia and seizures, and had greatly elevated glycine levels in their plasma and CSF. Molecular genetic analysis identified compound heterozygous variants in the GLDC gene in these three siblings, including a novel missense variant c.2680A > G (p.Thr894Ala) in exon 23 and a heterozygous deletion of exon 3, which were inherited respectively from their parents. In silico analysis, using several different types of bioinformatic software, predicted that the novel variant c.2680A > G in the GLDC gene was pathogenic. Moreover, the deletion of exon 3 was identified for the first time in a Chinese population.ConclusionsA novel missense variant and a previously reported deletion in GLDC gene were identified. The two variants of GLDC gene identified probably underlie the pathogenesis of non-ketotic hyperglycinemia in this family, and also enrich the mutational spectrum of GLDC gene.Electronic supplementary materialThe online version of this article (10.1186/s12881-017-0517-1) contains supplementary material, which is available to authorized users.

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Nonketotic hyperglycinemia: Functional assessment of missense variants inGLDCto understand phenotypes of the disease

Cited by 14 publications

References 46 publications

Genes and Variants Underlying Human Congenital Lactic Acidosis—From Genetics to Personalized Treatment

Genes and Variants Underlying Human Congenital Lactic Acidosis—From Genetics to Personalized Treatment

Large scale analyses of genotype-phenotype relationships of glycine decarboxylase mutations and neurological disease severity

A novel compound heterozygous variant identified in GLDC gene in a Chinese family with non-ketotic hyperglycinemia

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