Argininosuccinate lyase deficiency: mutational spectrum in Italian patients and identification of a novelASLpseudogene

Abstract

Communicated by William SlyArgininosuccinic aciduria (ASAuria) is an inborn error of metabolism caused by mutations in the argininosuccinate lyase (ASL) gene, which leads to the accumulation of argininosuccinic acid (ASA) in body fluids and severe hyperammonemia. A severe neonatal form and a milder late-onset variant are described. We report a novel ASL pseudogene located in the centromeric region of chromosome 7, 14 novel mutations in the ASL gene, and a novel intronic polymorphism found in a cohort of Italian patients. Our approach relied exclusively on genomic DNA analysis. We found seven missense mutations, two nonsense, three small insertions/deletions, and two splicing mutations. Only two patients harbored previously described mutations, and among the novel variants only two were present in more than one kindred. The pathogenicity of the splicing mutations was demonstrated by a functional splicing assay that employed a hybrid minigene. We also performed molecular modeling using the reported three-dimensional structure of ASL to predict the functional consequences of the missense mutations. There was no genotype-phenotype correlation. Patients with neonatal onset display developmental delay and seizures despite adequate metabolic control. Moreover, hepatomegaly, fibrosis, and abnormal liver function tests are common complications in these patients, but not in patients with the late infancy form. We stress the importance of mutation analysis in patients with ASAuria, to confirm the clinical diagnosis, and to perform DNA-based prenatal diagnosis in future pregnancies of these families. Hum Mutat 28(7), [694][695][696][697][698][699][700][701][702] 2007.

Two Novel Mutations in the Argininosuccinate Lyase Gene in Iranian Patients and Literature Review

“…In the absence of treatment, lethargy, seizures, and coma worsen, resulting in death (2). Our patients showed a typical neonatal form of ASA manifesting as vomiting, poor feeding, lethargy and respiratory distress, somnolence and seizures on the third and fourth 2 Iran J Pediatr. 2017; 27(3):e7666.…”

“…The ASL enzyme is a protein of 464 amino acids with a molecular weight of about 52 kD that is encoded by ASL gene. The human ASL gene was cloned in 1986 and is located on chromosome 7q11.21 it is about 35 kb in length and consists of 17 exons (of which 16 are protein-coding) with the first exon containing most of the 5 -untranslated region (2). Argininosuccinic aciduria (ASA, OMIM #207900) is a clinically heterogeneous, autosomal recessive disease due to ASL deficiency.…”

“…It was first reported by Solitare et al in 1969 (3). Two forms of ASA have been described: an early-onset, severe type and a late-onset type (2). In the severe form, signs and symptoms appear already after the first 24 hours after birth with vomiting, poor feeding, lethargy, respiratory distress which may all progress to coma and death if left untreated.…”

İnspiratuvar stridor klinik bulgusu ile saptanan argininosüksinik asidüri: yenidoğan olgusu

“…Because of nonspecific findings, mostly sepsis is considered and treatment is planned accordingly. However, transient moderate respiratory alkalosis attacks are important in terms of diagnosis in cases occuring during the neonatal period (9). Clinical deterioration usually proceeds rapidly and autonomic dysfunction or dysfunction of the neuromotor system including vasomotor imbalance, hypothermia, apnea, loss of tonus and reflexes develop (6).…”

Is CFTR 621+3 A>G a cystic fibrosis causing mutation?

“…After Total RNA was extracted and retrotranscribed as reported 7 PCR products were separated either on a 3% agarose gel or on a 12% acrilamyde gel. Individual bands were excised and sequenced using amplification primers as described.…”