Alternative titles; symbols
HGNC Approved Gene Symbol: AUH
SNOMEDCT: 237951008;
Cytogenetic location: 9q22.31 Genomic coordinates (GRCh38): 9:91,213,823-91,361,918 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9q22.31 | 3-methylglutaconic aciduria, type I | 250950 | Autosomal recessive | 3 |
The AUH gene encodes the mitochondrial enzyme 3-methylglutaconyl-CoA hydratase (EC 4.2.1.18), a key enzyme of leucine degradation (Ijlst et al., 2002).
Control of gene expression occurs by transcriptional and posttranscriptional regulation. The expression of certain protooncogenes and lymphokines is regulated by specific and rapid decay of their transcripts. Control mechanisms involve cis-acting elements found in the 3-prime untranslated region (UTR) and, in some examples, also in the coding region of mRNA. A common cis element found in the 3-prime UTR of rapidly decaying mRNAs is an AU-rich element (ARE), containing various numbers of reiterated AUUUA pentamers, at times associated with a general AU-richness with a surplus of uridylic residues. In hybrid constructs an ARE is able to confer rapid degradability to otherwise stable reporter transcripts. By using an AUUUA matrix, Nakagawa et al. (1995) affinity-purified a 32-kD protein, microsequenced it, and cloned the corresponding cDNA. In vitro, the recombinant protein bound specifically to AU-rich transcripts, including those for interleukin-3 (147740), granulocyte/macrophage colony-stimulating factor (138970), FOS (164810), and MYC (190080). Sequence analysis revealed an unexpected homology to enoyl-CoA hydratase (EC 4.2.1.17; see ECHS1; 602292), and the recombinant protein showed a low degree of enzymatic activity. Thus, this gene, designated AUH by Nakagawa et al. (1995), encodes an RNA-binding protein with intrinsic enzymatic activity. Protein immobilized on an AUUUA matrix was enzymatically active, suggesting that hydratase and AU-binding functions are located on different domains within a single polypeptide.
By heterologous expression in E. coli, Ijlst et al. (2002) showed that 3-methylglutaconyl-CoA hydratase, a key enzyme of leucine degradation, is encoded by the AUH gene.
Stumpf (2020) mapped the AUH gene to chromosome 9q22.31 based on an alignment of the AUH sequence (GenBank BC020722) with the genomic sequence (GRCh38).
3-Methylglutaconic aciduria type I (MGCA1; 250950) is an autosomal recessive disorder characterized clinically by various symptoms ranging from mild features, including delayed speech development and hyperchloremic acidosis associated with gastroesophageal reflux, to a more severe phenotype, including seizures and cerebellar abnormalities. The disorder is caused by deficiency of 3-methylglutaconyl-CoA hydratase, one of the key enzymes of leucine degradation. The enzyme deficiency results in elevated urinary levels of 3-methylglutaconic acid, 3-methylglutaric acid, and 3-hydroxyisovaleric acid. Mutation analysis of the AUH gene in 3 patients with this disorder revealed homozygosity for a nonsense (600529.0001) and a splice site (600529.0002) mutation (Ijlst et al., 2002).
Ly et al. (2003) reported that 3-methylglutaconyl-CoA hydratase is identical with the RNA-binding protein designated AUH, which possesses enoyl-CoA hydratase activity. They found that 5 patients with 3-methylglutaconic aciduria type I from 4 unrelated families had homozygosity or compound heterozygosity for mutations in the AUH gene. Clinical severity was variable. Complete absence of AUH appeared to be compatible with normal development in some cases. One patient, detected by neonatal screening, was 2 years old and asymptomatic; he was homozygous for an N-terminal frameshift mutation in the AUH gene (600529.0003). In a note added in proof, Ly et al. (2003) stated that a healthy younger sister had the same findings on newborn screening and was presumably affected, although clinically healthy.
In the patient with MGCA1 reported by Shoji et al. (1999), Matsumori et al. (2005) identified homozygosity for a splice site mutation (600529.0004).
In a Dutch woman with MGCA1, Wortmann et al. (2010) identified compound heterozygosity for 2 mutations in the AUH gene (G187S, 600529.0006 and G217D, 600529.0007).
In 2 Pakistani sibs, born to consanguineous parents, with MGCA1, Mercimek-Mahmutoglu et al. (2011) identified a homozygous deletion of exons 1-3 in the AUH gene (600529.0009). The mutation was found by PCR and Sanger sequencing of the AUH gene, which failed to amplify exons 1-3 in the sibs. The sibs had variable disease expressivity; the older sib had a learning disability, attention deficit-hyperactivity disorder, and leukoencephalopathy, and the younger sib had severe speech delay and normal cognitive abilities.
In 1 of 2 brothers from a nonconsanguineous Moroccan family who had 3-methylglutaconic aciduria type I (MGCA1; 250950) with speech development retardation as the only abnormality (Duran et al., 1982), Ijlst et al. (2002) identified a homozygous 589C-T transition in exon 5 of the AUH gene, resulting in an arg197-to-ter (R197X) substitution. The substitution caused translation to be terminated before glu209, which together with glu189 forms the catalytic group of the active-site pocket.
Ly et al. (2003) confirmed the R197X mutation in this family.
In a patient from a consanguineous Afghan family who had 3-methylglutaconic aciduria type I (MGCA1; 250950) with speech development as the presenting problem, Ijlst et al. (2002) identified a homozygous splice site mutation in the AUH gene, IVS8AS-1G-A. Delayed motor development became evident in retrospect in this patient (Ensenauer et al., 2000).
Ly et al. (2003) confirmed the IVS8AS-1G-A mutation in this family.
Eriguchi et al. (2006) identified a homozygous IVS8AS-1G-A mutation in a 55-year-old woman with type I MGCA who presented with forgetfulness, hyperreflexia, unsteady gait, cerebellar ataxia, dysarthria, and leukoencephalopathy.
In a boy born of first-cousin parents of Lebanese extraction who was found on newborn screening to have 3-methylglutaconic aciduria type I (MGCA1; 250950) (Wiley et al., 1999), Ly et al. (2003) identified a 1-bp deletion in exon 1 of the AUH gene, 80delG, that resulted in a frameshift mutation beginning at codon ser27. At 2.5 years of age he was healthy, with entirely normal growth and development. Ly et al. (2003) noted that his younger sister, likewise healthy, was found to have the same newborn screening findings indicative of the disorder.
Wortmann et al. (2010) provided follow-up of the Lebanese sibs reported by Ly et al. (2003). At ages 9 and 6.5 years, both had normal development and unremarkable physical examinations. Brain imaging was not performed.
In a Japanese boy with 3-methylglutaconic aciduria type I (MGCA1; 250950), born of consanguineous parents, previously reported by Shoji et al., 1999, Matsumori et al. (2005) identified a homozygous -2A-G transition in intron 1 of the AUH gene (IVS1AS-2A-G), resulting in the skipping of exon 2. The child had a severe form of the disorder with neurologic deterioration and metabolic acidosis. Each unaffected parent was heterozygous for the mutation.
In a German boy with 3-methylglutaconic aciduria type I (MGCA1; 250950), Illsinger et al. (2004) identified a homozygous -2A-G transition in intron 9 of the AUH gene (IVS9AS-2A-G). The child had normal psychomotor development but repeated febrile seizures.
Wortmann et al. (2010) reported follow-up of the German patient reported by Illsinger et al. (2004). At age 10 years, he showed normal development and attended regular school but had attention-deficit/hyperactivity disorder. Brain MRI showed mild signal abnormalities in the deep frontal white matter with sparing of the U-fibers. The authors suggested that these changes may represent the earliest stages of a slowly progressive neurodegenerative disorder.
In a Dutch woman with 3-methylglutaconic aciduria type I (MGCA1; 250950), Wortmann et al. (2010) identified compound heterozygosity for 2 mutations in the AUH gene: a 559G-A transition, resulting in a gly187-to-ser (G187S) substitution, and a 650G-A transition, resulting in a gly217-to-asp (G217D) substitution. Both mutations were predicted to abolish enzymatic activity by altering trimer formation and catalytic activity, and enzyme activity was virtually undetectable in fibroblasts and lymphocytes. The patient first developed progressive visual loss with optic atrophy at age 35, and developed dysarthria, limb ataxia, and gait ataxia over the following 16 years. Brain MRI at age 61 years showed extensive confluent white matter abnormalities in the supratentorial region with involvement of the deep and subcortical white matter, but sparing of the cerebellum and corpus callosum.
For discussion of the gly217-to-asp (G217D) mutation in the AUH gene that was found in compound heterozygous state in a patient with 3-methylglutaconic aciduria type I (MGCA1; 250950) by Wortmann et al. (2010), see 600529.0006.
In a man, born of consanguineous British parents, with 3-methylglutaconic aciduria type I (MGCA1; 250950), Wortmann et al. (2010) identified a homozygous 991A-T transversion, resulting in a lys331-to-ter (K331X) substitution, resulting in the production of an aberrant protein lacking the 8 terminal residues. The terminal part of the protein is necessary for the active-site pocket, for subunit interaction, and trimer stabilization. The patient had a complete deficiency of enzyme activity. He presented at age 30 years with mild cerebellar ataxia, which progressed to spastic paraparesis, nystagmus, and dementia over the next 29 years. Brain MRI at age 50 years showed extensive confluent white matter abnormalities in the supratentorial region with involvement of the deep and subcortical white matter, but sparing of the cerebellum and corpus callosum.
In 2 Pakistani sibs, born to consanguineous parents, with 3-methylglutaconic aciduria type I (MGCA1; 250950), Mercimek-Mahmutoglu et al. (2011) identified a homozygous deletion of exons 1-3 in the AUH gene. The mutation was identified by PCR and Sanger sequencing of the AUH gene, which failed to amplify exons 1-3 in both patients, but successfully amplified exons 1-3 of the AUH gene in the parents and an unaffected sib. 3-Methylglutaconyl-CoA hydratase enzyme activity was undetectable in fibroblasts from one of the sibs.
Duran, M., Beemer, F. A., Tibosch, A. S., Bruinvis, L., Ketting, D., Wadman, S. K. Inherited 3-methylglutaconic aciduria in two brothers--another defect of leucine metabolism. J. Pediat. 101: 551-554, 1982. [PubMed: 6181239] [Full Text: https://doi.org/10.1016/s0022-3476(82)80698-7]
Ensenauer, R., Muller, C. B., Schwab, K. O., Gibson, K. M., Brandis, M., Lehnert, W. 3-methylglutaconyl-CoA hydratase deficiency: a new patient with speech retardation as the leading sign. J. Inherit. Metab. Dis. 23: 341-344, 2000. [PubMed: 10896289] [Full Text: https://doi.org/10.1023/a:1005670911799]
Eriguchi, M., Mizuta, H., Kurohara, K., Kosugi, M., Yakushiji, Y., Okada, R., Yukitake, M., Hasegawa, Y., Yamaguchi, S., Kuroda, Y. 3-methylglutaconic aciduria type I causes leukoencephalopathy of adult onset. Neurology 67: 1895-1896, 2006. [PubMed: 17130438] [Full Text: https://doi.org/10.1212/01.wnl.0000244467.01362.54]
Ijlst, L., Loupatty, F. J., Ruiter, J. P. N., Duran, M., Lehnert, W., Wanders, R. J. A. 3-Methylglutaconic aciduria type I is caused by mutations in AUH. Am. J. Hum. Genet. 71: 1463-1466, 2002. Note: Erratum: Am. J. Hum. Genet. 73: 709 only, 2003. [PubMed: 12434311] [Full Text: https://doi.org/10.1086/344712]
Illsinger, S., Lucke, T., Zschocke, J., Gibson, K. M., Das, A. M. 3-methylglutaconic aciduria type I in a boy with fever-associated seizures. Pediat. Neurol. 30: 213-215, 2004. [PubMed: 15033206] [Full Text: https://doi.org/10.1016/j.pediatrneurol.2003.09.016]
Ly, T. B. N., Peters, V., Gibson, K. M., Liesert, M., Buckel, W., Wilcken, B., Carpenter, K., Ensenauer, R., Hoffmann, G. F., Mack, M., Zschocke, J. Mutations in the AUH gene cause 3-methylglutaconic aciduria type I. Hum. Mutat. 21: 401-407, 2003. [PubMed: 12655555] [Full Text: https://doi.org/10.1002/humu.10202]
Matsumori, M., Shoji, Y., Takahashi, T., Shoji, Y., Takada, G. A molecular lesion in a Japanese patient with severe phenotype of 3-methylglutaconic aciduria type I. Pediat. Int. 47: 684-686, 2005. [PubMed: 16354225] [Full Text: https://doi.org/10.1111/j.1442-200x.2005.02130.x]
Mercimek-Mahmutoglu, S., Tucker, T., Casey, B. Phenotypic heterogeneity in two siblings with 3-methylglutaconic aciduria type I caused by a novel intragenic deletion. Molec. Genet. Metab. 104: 410-413, 2011. [PubMed: 21840233] [Full Text: https://doi.org/10.1016/j.ymgme.2011.07.021]
Nakagawa, J., Waldner, H., Meyer-Monard, S., Hofsteenge, J., Jeno, P., Moroni, C. AUH, a gene encoding an AU-specific RNA binding protein with intrinsic enoyl-CoA hydratase activity. Proc. Nat. Acad. Sci. 92: 2051-2055, 1995. [PubMed: 7892223] [Full Text: https://doi.org/10.1073/pnas.92.6.2051]
Shoji, Y., Takahashi, T., Sawaishi, Y., Ishida, A., Matsumori, M., Shoji, Y., Enoki, M., Watanabe, H., Takada, G. 3-methylglutaconic aciduria type I: clinical heterogeneity as a neurometabolic disease. J. Inherit. Metab. Dis. 22: 1-8, 1999. [PubMed: 10070612] [Full Text: https://doi.org/10.1023/a:1005421111554]
Stumpf, A. M. Personal Communication. Baltimore, Md. 06/17/2020.
Wiley, V., Carpenter, K., Wilcken, B. Newborn screening with tandem mass spectrometry: 12 months' experience in NSW Australia. Acta Paediat. Suppl. 88: 48-51, 1999. [PubMed: 10626578] [Full Text: https://doi.org/10.1111/j.1651-2227.1999.tb01157.x]
Wortmann, S. B., Kremer, B. H., Graham, A., Willemsen, M. A., Loupatty, F. J., Hogg, S. L., Engelke, U. F., Kluijtmans, L. A., Wanders, R. J., Illsinger, S., Wilcken, B., Cruysberg, J. R., Das, A. M., Morava, E., Wevers, R. A. 3-methylglutaconic aciduria type I redefined: a syndrome with late-onset leukoencephalopathy. Neurology 75: 1079-1083, 2010. [PubMed: 20855850] [Full Text: https://doi.org/10.1212/WNL.0b013e3181f39a8a]