Identification of a novel R21X mutation in the liver-type arginase gene (ARG1) in four Portuguese patients with argininemia

Cardoso, Maria Luı́s; Martins, Esmeralda; Vasconcelos, Rui; Vilarinho, Laura; Rocha, Jorge

doi:10.1002/(sici)1098-1004(199910)14:4<355::aid-humu20>3.0.co;2-i

Cited by 17 publications

(8 citation statements)

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“…Most mutations are private. However, there is one report of a possible ethnicity-associated mutation (R21X) in four unrelated Portuguese patients (Cardoso et al 1999).…”

Section: Discussionmentioning

confidence: 99%

Hyperargininemia: A Family with a Novel Mutation in an Unexpected Site

et al. 2011

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Hyperargininemia is a rare autosomal recessive disorder of the last step of the urea cycle characterized by a deficiency in liver arginase1. Clinically, it differs from other urea cycle defects by a progressive paraparesis of the lower limbs (spasticity and contractures) with hyperreflexia, neurodevelopmental delay and regression in early childhood. Growth is affected as well. Hyperammonemia is episodic, if present at all. The disease is caused by mutations in the ARG1 gene; there are approximately 20 different known ARG1 mutations with considerable genetic heterogeneity. We describe two Arab siblings with a late diagnosis of hyperargininemia and present the genetic findings in their family. As ARG1 sequencing was unrevealing despite suggestive clinical and laboratory findings, molecular cDNA analysis was performed. The ARG1 expression pattern identified a 125-bp out-of-frame insertion between exons 3 and 4, leading to the addition of 41 amino acids and a premature termination codon TGA at the sixth codon downstream. The insertion originated at intron 3 and was attributable to a novel c.305 + 1323 t > c intronic base change that enabled an enhancement phenomenon. This is the first reported exon-splicing-enhancer mutation in patients with hyperargininemia. The clinical course and genetic findings emphasize the possibility that hyperargininemia causes neurological deterioration in children and the importance of analyzing the expression pattern of the candidate gene when sequencing at the DNA level is unrevealing.

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“…Most mutations are private. However, there is one report of a possible ethnicity-associated mutation (R21X) in four unrelated Portuguese patients (Cardoso et al 1999).…”

Section: Discussionmentioning

confidence: 99%

Hyperargininemia: A Family with a Novel Mutation in an Unexpected Site

et al. 2011

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“…Including all published (Amayreh et al., ; Brockstedt, Smit, de Grauw, van der Klei‐van Moorsel, & Jakobs, ; Cardoso et al., ; Carvalho et al., ; Cohen et al., ; Edwards et al., ; Haraguchi et al., ; Hertecant et al., ; Huemer et al., ; Häberle & Koch, ; Jain‐Ghai et al., ; Korman et al., ; Kuster et al., ; Lambert et al., ; Lee et al., ; Mullane et al., ; Mustafa et al., ; Rodrigues, Martins, Ferreira, Vilarinho, & Leao Teles, ; Schiff et al., ; Scholl‐Bürgi et al., ; Segawa et al., ; Sin et al., ; Snyderman, Sansaricq, Chen, Norton, & Phansalkar, ; Snyderman, Sansaricq, Norton, & Goldstein, ; Tsang et al., ; Uchino et al., ; Uchino et al., ; Villegas‐Ruiz et al., ; Vockley et al., ,b; Vockley et al., ; Wu et al., ; Wu et al., ; Zhang et al., ) and novel cases, 66 mutations in ARG1 from 112 patients are compiled here (Tables and , Figures C and A). All of these mutations have been included in the LOVD database (https://databases.lovd.nl/shared/variants/ARG1/unique).…”

Section: Variantsmentioning

confidence: 99%

“…The ARG1 gene spans 11.1 kb, maps to 6q23, has an open reading frame of 1,393 bp and harbors eight exons. The ∼50 disease‐associated mutations reported so far (Amayreh, Meyer, & Das, ; Cardoso, Martins, Vasconcelos, Vilarinho, & Rocha, ; Carvalho et al., ; Cohen et al., ; Edwards et al., ; Haraguchi et al., ; Hertecant, Al‐Gazali, Karuvantevida, & Ali, ; Häberle & Koch, ; Jain‐Ghai, Nagamani, Blaser, Siriwardena, & Feigenbaum, ; Korman et al., ; Kuster, Benoist, Caillaux, Muller, & Acquaviva, ; Lee, Jin, Kim, Choi, & Yoo, ; Mullane, Errico, & Evans, ; Mustafa et al., ; Schiff et al., ; Scholl‐Bürgi et al., ; Segawa et al., ; Tsang et al., ; Uchino et al., ; Uchino et al., ; Vockley et al., ,b; Vockley et al., ; Wu et al., ; Wu et al., ) spread out across the eight exons and at some exon–intron boundary splice sites. In this article, we compile all published mutations and all mutations recently identified in our laboratory.…”

Section: Introductionmentioning

confidence: 99%

Mutations and common variants in the human arginase 1 (ARG1) gene: Impact on patients, diagnostics, and protein structure considerations

et al. 2018

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The urea cycle disorder argininemia is caused by a defective arginase 1 (ARG1) enzyme resulting from mutations in the ARG1 gene. Patients generally develop hyperargininemia, spastic paraparesis, progressive neurological and intellectual impairment, and persistent growth retardation. Interestingly, in contrast to other urea cycle disorders, hyperammonemia is rare. We report here 66 mutations (12 of which are novel), including 30 missense mutations, seven nonsense, 10 splicing, 15 deletions, two duplications, one small insertion, and one translation initiation codon mutation. For the most common mutations (p.Thr134Ile, p.Gly235Arg and p.Arg21*), which cluster geographically in Brazil, China, or Turkey, a structural rationalization of their effect has been included. In order to gain more knowledge on the disease, we have collected clinical and biochemical information of 112 patients, including the patients' genetic background and ethnic origin. We have listed as well the missense variants with unknown relevance. For all missense variants (of both known and unknown relevance), the conservation, severity prediction, and ExAc scores have been included. Lastly, we review ARG1 regulation, animal models, diagnostic strategies, newborn screening, prenatal testing, and treatment options.

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“…Standard mutation analysis using DNA from whole blood cells is suitable and to date more than 20 different mutations of the ARG1 gene are known [82][83][84][85][86]. Mutation analysis on RNA level using the constitutively expressed ARG1 transcripts of granulocytes has recently been published [87].…”

Section: Mutation Analysis Of the Arg1 Genementioning

confidence: 99%

Mutation analysis of urea cycle disorders

Häberle

Rüfenacht

2016

J Pediatr Biochem

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Urea cycle disorders (UCDs) are a group of autosomal or X-linked, recessively inherited errors of metabolism that lead to severe neurological disease due to insufficient detoxification of excess nitrogen. The resulting hyperammonemia is the key feature of UCDs, but at the same time only a surrogate marker. In the majority of cases, a sole biochemical analysis is indicative but not diagnostic. Therefore, additional means are required and mutation analysis is the method of choice for confirmation in most cases of UCD. In addition to confirming the diagnosis, mutation analysis enables genetic counseling and prenatal testing and contributes to new research approaches. All genes involved in any of the enzymatic (namely the genes for N-acetylglutamate synthase, NAGS; carbamoylphosphate synthetase, CPS1; ornithine transcarbamylase, OTC; argininosuccinate synthetase, ASS1; argininosuccinate lyase, ASL; arginase, ARG1) or transporter steps (namely the genes for the ornithine/citrulline antiporter ORNT1, SLC25A15; glutamate/aspartate antiporter citrin, SLC25A13) of the urea cycle are known and thus accessible for genetic testing. In most situations, direct Sanger sequencing using DNA from peripheral blood cells can be done but there are exceptions to this such as in the case of the relatively large CPS1 gene which renders RNA based mutation analysis an attractive alternative. With this review, we provide an overview on the current methods used for mutation analysis of each UCD gene, we mention possible pitfalls and their solutions, and discuss alternative methods which may become standard in the future.

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Identification of a novel R21X mutation in the liver-type arginase gene (ARG1) in four Portuguese patients with argininemia

Cited by 17 publications

References 5 publications

Hyperargininemia: A Family with a Novel Mutation in an Unexpected Site

Hyperargininemia: A Family with a Novel Mutation in an Unexpected Site

Mutations and common variants in the human arginase 1 (ARG1) gene: Impact on patients, diagnostics, and protein structure considerations

Mutation analysis of urea cycle disorders

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