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NGS in argininosuccinic aciduria detects a mutation (D145G) which drives alternative splicing of ASL: a case report study.

ABSTRACT: Argininosuccinic aciduria (ASAuria; OMIM 207900) is a rare autosomal recessive heterogeneous urea cycle disorder, which leads to the accumulation of argininosuccinic acid in the blood and urine. We aimed to perform genetic test to the patient and help clinician to diagnose precisely.In this study, we use next generation sequencing (NGS) and exon trapping to analysis the family members. We identified compound heterozygous mutations of the argininosuccinate lyase (ASL) gene in a Chinese Han ASAuria patient. The c.434A>G (p.(D145G)) mutation in exon 5 was shown by exon trapping to select for the formation of an alternative transcript deleted for exon 5. The c.1366C>T (p.(R456W)) mutation had been previously reported in an Italian patient.This is the first report of a missense mutation driving alternative splicing which results in the loss of exon 5 in ASAuria. This study also demonstrates the value of NGS in the identification of mutations and molecular diagnosis for ASAuria families.

SUBMITTER: Wen W

PROVIDER: S-EPMC4739340 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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NGS in argininosuccinic aciduria detects a mutation (D145G) which drives alternative splicing of ASL: a case report study.

Wen Wei W Yin Dan D Huang Fangfang F Guo Meng M Tian Tian T Zhu Hui H Yang Yun Y

BMC medical genetics 20160203

<h4>Background</h4>Argininosuccinic aciduria (ASAuria; OMIM 207900) is a rare autosomal recessive heterogeneous urea cycle disorder, which leads to the accumulation of argininosuccinic acid in the blood and urine. We aimed to perform genetic test to the patient and help clinician to diagnose precisely.<h4>Case presentation</h4>In this study, we use next generation sequencing (NGS) and exon trapping to analysis the family members. We identified compound heterozygous mutations of the argininosucci ...[more]

PMID: 26843370

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Project description:The urea cycle consists of six consecutive enzymatic reactions that convert waste nitrogen into urea. Deficiencies of any of these enzymes of the cycle result in urea cycle disorders (UCD), a group of inborn errors of hepatic metabolism that often result in life threatening hyperammonemia. Argininosuccinate lyase (ASL) is a cytosolic enzyme which catalyzes the fourth reaction in the cycle and the first degradative step, that is, the breakdown of argininosuccinic acid to arginine and fumarate. Deficiency of ASL results in an accumulation of argininosuccinic acid in tissues, and excretion of argininosuccinic acid in urine leading to the condition argininosuccinic aciduria (ASA). ASA is an autosomal recessive disorder and is the second most common UCD. In addition to the accumulation of argininosuccinic acid, ASL deficiency results in decreased synthesis of arginine, a feature common to all UCDs except argininemia. Arginine is not only the precursor for the synthesis of urea and ornithine as part of the urea cycle but it is also the substrate for the synthesis of nitric oxide, polyamines, proline, glutamate, creatine, and agmatine. Hence, while ASL is the only enzyme in the body able to generate arginine, at least four enzymes use arginine as substrate: arginine decarboxylase, arginase, nitric oxide synthetase (NOS) and arginine/glycine aminotransferase. In the liver, the main function of ASL is ureagenesis, and hence, there is no net synthesis of arginine. In contrast, in most other tissues, its role is to generate arginine that is designated for the specific cell's needs. While patients with ASA share the acute clinical phenotype of hyperammonemia, encephalopathy, and respiratory alkalosis common to other UCD, they also present with unique chronic complications most probably caused by a combination of tissue specific deficiency of arginine and/or elevation of argininosuccinic acid. This review article summarizes the clinical characterization, biochemical, enzymatic, and molecular features of this disorder. Current treatment, prenatal diagnosis, diagnosis through the newborn screening as well as hypothesis driven future treatment modalities are discussed.

Project description:ObjectivesThis UK-wide study defines the natural history of argininosuccinic aciduria and compares long-term neurological outcomes in patients presenting clinically or treated prospectively from birth with ammonia-lowering drugs.MethodsRetrospective analysis of medical records prior to March 2013, then prospective analysis until December 2015. Blinded review of brain MRIs. ASL genotyping.ResultsFifty-six patients were defined as early-onset (n = 23) if symptomatic < 28 days of age, late-onset (n = 23) if symptomatic later, or selectively screened perinatally due to a familial proband (n = 10). The median follow-up was 12.4 years (range 0-53). Long-term outcomes in all groups showed a similar neurological phenotype including developmental delay (48/52), epilepsy (24/52), ataxia (9/52), myopathy-like symptoms (6/52) and abnormal neuroimaging (12/21). Neuroimaging findings included parenchymal infarcts (4/21), focal white matter hyperintensity (4/21), cortical or cerebral atrophy (4/21), nodular heterotopia (2/21) and reduced creatine levels in white matter (4/4). 4/21 adult patients went to mainstream school without the need of additional educational support and 1/21 lives independently. Early-onset patients had more severe involvement of visceral organs including liver, kidney and gut. All early-onset and half of late-onset patients presented with hyperammonaemia. Screened patients had normal ammonia at birth and received treatment preventing severe hyperammonaemia. ASL was sequenced (n = 19) and 20 mutations were found. Plasma argininosuccinate was higher in early-onset compared to late-onset patients.ConclusionsOur study further defines the natural history of argininosuccinic aciduria and genotype-phenotype correlations. The neurological phenotype does not correlate with the severity of hyperammonaemia and plasma argininosuccinic acid levels. The disturbance in nitric oxide synthesis may be a contributor to the neurological disease. Clinical trials providing nitric oxide to the brain merit consideration.

Dataset Information

NGS in argininosuccinic aciduria detects a mutation (D145G) which drives alternative splicing of ASL: a case report study.

Publications

NGS in argininosuccinic aciduria detects a mutation (D145G) which drives alternative splicing of ASL: a case report study.

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