Mutations and DNA diagnoses of classical citrullinemia

Mutations and polymorphisms in the human argininosuccinate synthetase (ASS1) gene

“…A total of 17 mutations have been shown to cause neonatal onset of the disorder when found in a homozygous state (see Table 1) [Gao et al, 2003;Kakinoki et al, 1997;Kleijer et al, 2006;Kobayashi et al, 1990Kobayashi et al, , 1991Kobayashi et al, , 1994Kobayashi et al, , 1995Sander et al, 2003;Vilaseca et al, 2001]: among them are two nonsense mutations in addition to four splice-site defects, two deletions, and seven missense mutations. However, compound heterozygous carriers of some of these mutations (Ivs15-1G4C, R157C, V263M, E283K, G324S, R363W, and G390R) have been identified who, owing to the function of the second allele, present only mild clinical symptoms [Gao et al, 2003;Häberle et al, 2002;Hong et al, 2000;Sander et al, 2003].…”

“…However, compound heterozygous carriers of some of these mutations (Ivs15-1G4C, R157C, V263M, E283K, G324S, R363W, and G390R) have been identified who, owing to the function of the second allele, present only mild clinical symptoms [Gao et al, 2003;Häberle et al, 2002;Hong et al, 2000;Sander et al, 2003]. A total of 30 mutations occur in compound heterozygotes with neonatal onset of citrullinemia [Gao et al, 2003;Häberle et al, 2002;Kakinoki et al, 1997;Kleijer et al, 2006;Kobayashi et al, 1990Kobayashi et al, , 1991Kobayashi et al, , 1994Li et al, 2001;Vilaseca et al, 2001]. Again, some of these aberrations-such as G14S, G117D, and E191Q-were also revealed to account for mild or late onset forms of the disease.…”

“…Since the ASS gene was cloned by Bock et al [1983] and studies on the human ASS mRNA showed that due to mRNA stability mutations in this gene could easily be detected by PCR methods [Kobayashi et al, 1990], mutations in the ASS gene have been described in an increasing number of families [Ban et al, 2001;Gao et al, 2003;Häberle et al, 2002Häberle et al, , 2003Hong et al, 2000;Kakinoki et al, 1997;Kleijer et al, 2006;Kobayashi et al, 1990Kobayashi et al, , 1991Kobayashi et al, , 1994Li et al, 2001;Ruitenbeek et al, 2003;Sander et al, 2003;Vilaseca et al, 2001]. As outlined above, the clinical presentation is very heterogeneous, ranging from neonatal metabolic decompensation due to fatal hyperammonemia in cases of mild disease with mainly a biochemical phenotype to adult onset of symptoms related to hyperammonemia and citrullinemia.…”

“…Skin fibroblasts or liver tissue must be consulted for mRNA analysis [Häberle et al, 2002;Kobayashi et al, 1994] since the existence of numerous pseudogenes does not allow production of mRNA from whole blood cells [Beaudet et al, 1982;Su et al, 1984;Todd and Naylor, 1992]. However, genomic DNA can be extracted from peripheral blood cells and serve as a source for the amplification of intronic and exonic sequences [Augoustides-Savvopoulou et al, 2000;Häberle et al, 2002;Kakinoki et al, 1997;Kobayashi et al, 1990Kobayashi et al, , 1991Kobayashi et al, , 1994Kobayashi et al, , 1995Ruitenbeeck et al, 2003;Vilaseca et al, 2001]. For prenatal testing, molecular genetic means can be regarded as the most reliable method if the disease-causing mutation is known [Häberle and Koch, 2004].…”

Mitochondrial aspartate glutamate carrier (citrin) deficiency as the cause of adult-onset type II citrullinemia (CTLN2) and idiopathic neonatal hepatitis (NICCD)

“…Later, Saheki et al (1980Saheki et al ( , 1981 reported that the enzyme abnormalities of citrullinemia can be classified as qualitative (type I) or quantitative (type II), and that in type I, ASS is affected not only in the liver but also in the kidney and in cultured fibroblast cells, and is kinetically abnormal, while in type II, ASS is affected only in the liver (Saheki et al 1982(Saheki et al , 1983a, where it is deficient but kinetically normal and has the same specific activity as the control. Further research showed that type I citrullinemia, together with type III, in which ASS is almost completely absent in every cell where the ASS gene is expressed (Saheki et al 1985a(Saheki et al , 1987aImamura et al 1987), is caused by mutations in the ASS gene (Kobayashi et al , 1990(Kobayashi et al , 1991(Kobayashi et al , 1994(Kobayashi et al , 1995aKakinoki et al 1997;Vilaseca et al 2001). Kinetically abnormal mutant ASS is found in patients with type I citrullinemia, and mainly splicing mutations, but not missense mutations, cause type III citrullinemia (Kobayashi et al , 1994(Kobayashi et al , 1995a.…”