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Two hypomorphic alleles of mouse Ass1 as a new animal model of citrullinemia type I and other hyperammonemic syndromes.

ABSTRACT: Citrullinemia type I (CTLN1, OMIM# 215700) is an inherited urea cycle disorder that is caused by an argininosuccinate synthetase (ASS) enzyme deficiency. In this report, we describe two spontaneous hypomorphic alleles of the mouse Ass1 gene that serve as an animal model of CTLN1. These two independent mouse mutant alleles, also described in patients affected with CTLN1, interact to produce a range of phenotypes. While some mutant mice died within the first week after birth, others survived but showed severe retardation during postnatal development as well as alopecia, lethargy, and ataxia. Notable pathological findings were similar to findings in human CTLN1 patients and included citrullinemia and hyperammonemia along with delayed cerebellar development, epidermal hyperkeratosis, and follicular dystrophy. Standard treatments for CTLN1 were effective in rescuing the phenotype of these mutant mice. Based on our studies, we propose that defective cerebellar granule cell migration secondary to disorganization of Bergmann glial cell fibers cause cerebellar developmental delay in the hyperammonemic and citrullinemic brain, pointing to a possible role for nitric oxide in these processes. These mouse mutations constitute a suitable model for both mechanistic and preclinical studies of CTLN1 and other hyperammonemic encephalopathies and, at the same time, underscore the importance of complementing knockout mutations with hypomorphic mutations for the generation of animal models of human genetic diseases.

SUBMITTER: Perez CJ

PROVIDER: S-EPMC2947290 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Two hypomorphic alleles of mouse Ass1 as a new animal model of citrullinemia type I and other hyperammonemic syndromes.

Perez Carlos J CJ Jaubert Jean J Guénet Jean-Louis JL Barnhart Kirstin F KF Ross-Inta Catherine M CM Quintanilla Vicente C VC Aubin Isabelle I Brandon Jimi L JL Otto Nancy W NW DiGiovanni John J Gimenez-Conti Irma I Giulivi Cecilia C Kusewitt Donna F DF Conti Claudio J CJ Benavides Fernando F

The American journal of pathology 20100819 4

Citrullinemia type I (CTLN1, OMIM# 215700) is an inherited urea cycle disorder that is caused by an argininosuccinate synthetase (ASS) enzyme deficiency. In this report, we describe two spontaneous hypomorphic alleles of the mouse Ass1 gene that serve as an animal model of CTLN1. These two independent mouse mutant alleles, also described in patients affected with CTLN1, interact to produce a range of phenotypes. While some mutant mice died within the first week after birth, others survived but s ...[more]

PMID: 20724589

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Project description:BackgroundCitrullinemia type I (CTLN1, MIM #215700) is an autosomal recessive urea cycle disorder caused by deficiency of argininosuccinate synthase (ASS). CTLN1 is characterized by life-threatening hyperammonemia and risk for resulting neurocognitive impairments. The diagnosis of CTLN1 is confirmed by the identification of biallelic pathogenic variants in the ASS1 gene. However, there are a small percentage of CTLN1 patients with a characteristic biochemical phenotype without identifiable variants in ASS1. We describe the molecular characterization of two related Romani children with biochemically diagnosed CTLN1, whose clinical genetic testing failed to detect any pathogenic variant in ASS1.MethodsGenomic DNA was extracted from peripheral blood lymphocytes collected from both patients. Sanger sequencing was performed after PCR amplifications of 5'- and 3'-untranslated regions of the ASS1 gene. A luciferase reporter assay was performed using the human malignant melanoma A2058 cell line and the human liver cancer cell line HepG2.ResultsWe interrogated the non-coding regions of ASS1 by targeted PCR amplification and identified a homozygous 477-bp microdeletion in the promoter region of the ASS1 gene in both patients. Heterozygosity of the variant was confirmed in their parents. Sanger sequencing confirmed the microdeletion contained the entire sequence of the non-coding exon 1 of ASS1 that includes promoter elements of GC-box, E-box, AP2-binding site, and TATA-box. Luciferase reporter assay using an expression plasmid containing the wild-type or mutant ASS1 sequences showed robust reporter expression from the wild-type sequence and significantly reduced expression driven by the mutant insert (3.6% in A2058 cells and 3.3% in HepG2 cells). These findings were consistent with the hypothesis that the microdeletion identified in the patients disrupted an essential promoter element and resulted in deficiency of ASS1 mRNA expression.ConclusionsThis is the first report of CTLN1 patients caused by a Romani microdeletion variant affecting the non-coding upstream sequence of ASS1. Ablation of the promoter sequence can cause CTLN1 by the reduction of ASS1 expression. Currently available clinical sequencing methods usually do not cover the promoter sequence including the non-coding exon of ASS1, highlighting the importance of evaluating this region in genetic testing for CTLN1.

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Two hypomorphic alleles of mouse Ass1 as a new animal model of citrullinemia type I and other hyperammonemic syndromes.

Publications

Two hypomorphic alleles of mouse Ass1 as a new animal model of citrullinemia type I and other hyperammonemic syndromes.

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