Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.5.1.4 (deaminase)
 5,113 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Aspartylglucosaminuria (AGU) is exceptional among lysosomal storage diseases since it represents the only known amidase deficiency in man, being caused by an inadequate function of aspartylglucosaminidase (AGA, E.C. 3.5.1.26.). This amidase is essential in one of the final steps in the ordered breakdown of glycoproteins since it cleaves Asn from the residual N-acetylglucosamines (for reviews see 1, 2). The deficiency of the enzyme activity results in the typical lysosomal accumulation of the abnormal degradation products (mainly aspartylglucosamine, 2-acetamido-1-beta-L-aspartamido-1,2-dideoxyglucose) in patients' cells and tissues. The diagnosis of AGU has so far been based on the detection of abnormal metabolites in urine and decreased enzyme activity in the cultured fibroblasts or isolated lymphocytes. Prenatal diagnosis has been possible by demonstrating the deficient enzyme activity of amniocytes or chorion villus biopsies. Identification of carriers has been difficult and unreliable due to the high individual variation in AGA activity and prerequisite for isolated blood lymphocytes. During the past few years we have purified the human enzyme into homogeneity, isolated the full length cDNA and characterized the majority of AGU mutations in this cDNA. This work facilitated the development of a reliable DNA diagnostic test suitable also for large scale carrier screening. The molecular pathology of the most common AGU mutation was unravelled, this being a prerequisite for the oncoming developments for therapy. Although AGU is a relatively rare disease, characterization of the AGU mutations and their cellular consequences have revealed highly interesting new phenomena in the biosynthesis of this lysosomal enzyme, some of which carry general biological significance.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Dissection of the molecular pathology of aspartylglucosaminuria provides the basis for DNA diagnostics and future therapeutic interventions. 832 15

1. This manuscript describes two different strategies to progress from the clinical assessment of patients to the identification of disease-causing mutations. In the first disease, recognition of a metabolic abnormality allowed direct molecular analysis of the causal gene. In contrast, localization of the second disease gene by linkage analysis was critical to implicate a gene with a previously unsuspected disease role. 2. Two sisters with chronic respiratory disease and recurrent infections were identified as the first cases of adult onset immunodeficiency due to adenosine deaminase deficiency. Autosomal recessive inheritance of two mutations in the adenosine deaminase gene was demonstrated. Enzyme replacement therapy improved the patients' immunological and clinical status. 3. Individuals with pulmonary arteriovenous malformations were used to identify families with hereditary haemorrhagic telangiectasia (HHT, Rendu-Osler-Weber Syndrome). Linkage studies mapped the HHT disease gene in some families to chromosome 9, and demonstrated genetic heterogeneity. The chromosome 9 disease interval was refined, and several candidate genes were assessed. Following the first description of disease-segregating mutations, a complete analysis of the endoglin gene (which encodes an endothelial cell transforming growth factor-beta receptor) identified seven novel mutations. Two mutations did not produce mutant mRNA, and disease severity was comparable between families, indicating that HHT results from stoichiometric insufficiency of endoglin. 4. Each study has implications extending beyond the relatively rare disease analysed. The adenosine-deaminase-deficient patients highlight a treatable cause of HIV-negative CD4+ lymphopenia in adults, perhaps accounting for further cases of 'non-HIV AIDS'. The HHT studies have illuminated a novel area of vascular pathophysiology, with potential relevance to further disease states.
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PMID:Glaxo/MRS Young Investigator Medal. Molecular studies on adenosine deaminase deficiency and hereditary haemorrhagic telangiectasia. 961 53

Objective: Inherited myopathies comprise more than 200 different individually rare disease-subtypes, but when combined together they have a high prevalence of 1 in 6,000 individuals across the world. Our goal was to determine for the first time the clinical- and gene-variant spectrum of genetic myopathies in a substantial cohort study of the Indian subcontinent. Methods: In this cohort study, we performed the first large clinical exome sequencing (ES) study with phenotype correlation on 207 clinically well-characterized inherited myopathy-suspected patients from the Indian subcontinent with diverse ethnicities. Results: Clinical-correlation driven definitive molecular diagnosis was established in 49% (101 cases; 95% CI, 42-56%) of patients with the major contributing pathogenicity in either of three genes, GNE (28%; GNE-myopathy), DYSF (25%; Dysferlinopathy), and CAPN3 (19%; Calpainopathy). We identified 65 variant alleles comprising 37 unique variants in these three major genes. Seventy-eight percent of the DYSF patients were homozygous for the detected pathogenic variant, suggesting the need for carrier-testing for autosomal-recessive disorders like Dysferlinopathy that are common in India. We describe the observed clinical spectrum of myopathies including uncommon and rare subtypes in India: Sarcoglycanopathies (SGCA/B/D/G), Collagenopathy (COL6A1/2/3), Anoctaminopathy (ANO5), telethoninopathy (TCAP), Pompe-disease (GAA), Myoadenylate-deaminase-deficiency-myopathy (AMPD1), myotilinopathy (MYOT), laminopathy (LMNA), HSP40-proteinopathy (DNAJB6), Emery-Dreifuss-muscular-dystrophy (EMD), Filaminopathy (FLNC), TRIM32-proteinopathy (TRIM32), POMT1-proteinopathy (POMT1), and Merosin-deficiency-congenital-muscular-dystrophy-type-1 (LAMA2). Thirteen patients harbored pathogenic variants in >1 gene and had unusual clinical features suggesting a possible role of synergistic-heterozygosity/digenic-contribution to disease presentation and progression. Conclusions: Application of clinically correlated ES to myopathy diagnosis has improved our understanding of the clinical and genetic spectrum of different subtypes and their overlaps in Indian patients. This, in turn, will enhance the global gene-variant-disease databases by including data from developing countries/continents for more efficient clinically driven molecular diagnostics.
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PMID:Clinical and Genomic Evaluation of 207 Genetic Myopathies in the Indian Subcontinent. 3325 Aug 42