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Human Genetics

, Volume 110, Issue 4, pp 327–333 | Cite as

Structure of the human argininosuccinate synthetase gene and an improved system for molecular diagnostics in patients with classical and mild citrullinemia

  • J. Häberle
  • S. Pauli
  • M. Linnebank
  • W. Kleijer
  • H. Bakker
  • R. Wanders
  • E. Harms
  • H. Koch
Original Investigation

Abstract.

Deficiency of argininosuccinate synthetase (ASS) causes citrullinemia, an autosomal recessive inherited defect of the urea cycle. Most patients described so far have presented with the classical form of the disease. There are also patients with a mild form of citrullinemia in whom the exact molecular basis and clinical relevance are uncertain. Mutations in the human ASS gene have not yet been described in mildly affected or asymptomatic patients with citrullinemia. The genomic sequence of the human ASS gene is not precisely known making mutation analysis difficult. Here, the entire genomic DNA sequence and mutations in the ASS gene of patients with the classical and mild form of the disease are described. The mutations c.1168G→A (G390R) and IVS13+5 G→A and the novel mutation c.323G→T (R108L) have been found to be associated with classical citrullinemia, whereas the novel mutations c.535T→G (W179R), and c.1085G→T (G362V) have been detected on alleles of the mildly affected patients. Thus, mutations found in the human ASS gene of asymptomatic children with biochemical abnormalities and in some cases enzymatically proven citrullinemia have allowed us to classify these cases as ASS-deficient patients. The elucidation of the structure of the human ASS gene has made possible the use of intronic primers for molecular analysis of patients with mild disease and the classical form, and provides another option for prenatal diagnostics in affected families with the severe type.

Keywords

Citrulline None None Newborn Screening Program Citrulline Level Plasma Citrulline 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Springer-Verlag 2002

Authors and Affiliations

  • J. Häberle
    • 1
  • S. Pauli
    • 1
  • M. Linnebank
    • 1
  • W. Kleijer
    • 2
  • H. Bakker
    • 3
  • R. Wanders
    • 3
  • E. Harms
    • 1
  • H. Koch
    • 1
  1. 1.Klinik und Poliklinik für Kinderheilkunde, Universitätsklinikum Münster, Albert-Schweitzer-Str. 33, 48149 MünsterGermany
  2. 2.Clinical Genetics, University Hospital Dijkzigt, Erasmus University, RotterdamThe Netherlands
  3. 3.Academic Medical Centre, University of Amsterdam, AmsterdamThe Netherlands

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