Mutations in the BH₄-metabolizing genes GTP cyclohydrolase I, 6-pyruvoyl-tetrahydropterin synthase, sepiapterin reductase, carbinolamine-4a-dehydratase, and dihydropteridine reductase

Abstract

Tetrahydrobiopterin (BH(4)) deficiencies are a highly heterogeneous group of disorders with several hundred patients, and so far a total of 193 different mutant alleles or molecular lesions identified in the GTP cyclohydrolase I (GTPCH), 6-pyruvoyl-tetrahydropterin synthase (PTPS), sepiapterin reductase (SR), carbinolamine-4a-dehydratase (PCD), or dihydropteridine reductase (DHPR) genes. The spectrum of mutations causing a reduction in one of the three biosynthetic (GTPCH, PTPS, and SR) or the two regenerating enzymes (PCD and DHPR) is tabulated and reviewed. Furthermore, current genomic variations or SNPs are also compiled. Mutations in GCH1 are scattered over the entire gene, and only 5 out of 104 mutant alleles, present in a homozygous state, are reported to cause the autosomal recessive form of inheritable hyperphenylalaninemia (HPA) associated with monoamine neurotransmitter deficiency. Almost all other 99 different mutant alleles in GCH1 are observed together with a wild-type allele and cause Dopa-responsive dystonia (DRD, Segawa disease) in a dominant fashion with reduced penetrance. Compound heterozygous or homozygous mutations are spread over the entire genes for PTS with 44 mutant alleles, for PCBD with nine mutant alleles, and for QDPR with 29 mutant alleles. These mutations cause an autosomal recessive inherited form of HPA, mostly accompanied by a deficiency of the neurotransmitters dopamine and serotonin. Lack of sepiapterin reductase activity, an autosomal recessive variant of BH(4) deficiency presenting without HPA, was diagnosed in patients with seven different mutant alleles in the SPR gene in exons 2 or 3 or in intron 2. Details on all mutations presented here are constantly updated in the BIOMDB database (www.bh4.org).

Chaperone-Like Therapy with Tetrahydrobiopterin in Clinical Trials for Phenylketonuria: Is Genotype a Predictor of Response?

“…All data for all subjects and all components of these clinical trials are available in Supplementary Table 1. BH 4 is the catalytic cofactor for several enzymes, including PAH, and mutations exist that impair the enzymes serving synthesis and recycling of BH 4 (Thony and Blau 2006); these Mendelian disorders of BH 4 metabolism can be treated by sapropterin replacement therapy. The metabolic responsiveness of our subset of sapropterin-responsive HPA/PKU patients is explained by a different process, namely enhancement of residual PAH enzyme activity and opening of the oxidative pathway (Muntau et al 2002).…”

Mutation spectrum of and founder effects affecting the PTS gene in East Asian populations

“…The c.259C4T, c.272A4G and c.286G4A mutations have only been reported in Asian populations, whereas the c.155A4G mutation has been observed in western countries. 12,17 More than 89.7% (158/176) of the patients carried at least one of the five common mutations suggesting that screening for these common mutations should be an early step in the treatment of PTPS-deficient patients from East Asia. The distribution of the common mutations differs from population to population.…”

“…More than 53 PTS mutations, including missense mutations, nonsense mutations, splicing error mutations and small insertion/deletions, which are spread over the six exons and the first three introns, have been described in various different populations. 12 In this study, a molecular analysis of the PTS gene was performed on populations in East Asia, including the Han populations in Taiwan, Mainland China and Malaysia as well as the populations of Japan, South Korea, Thailand and the Philippines. A total of 43 different PTS gene mutations were observed.…”

Commentary on the mutation spectrum of and founder effects affecting the PTS gene in East-Asian populations

“…3 The incidence of BH4 deficiency is at 1 in 1 000 000, except that in Taiwanese (much higher than that in Japanese and in Caucasians). 5,6 Liu et al 7 reported that the BH4-deficient HPA was estimated to make up around 30% of the Chinese population in Taiwan suffering from HPA, which is much higher than in Caucasian populations (1.5-2% of HPA). In Taiwan approximately 86% of BH4-deficient HPA in the Chinese population was found to be caused by PTPS deficiency, although it is the most common form of BH4 deficiency in the world.…”

“…5 In previous issue of the Journal, Chiu et al 8 investigated mutations in the patients with PTPS (gene symbol: PTS) deficiency in East-Asian populations and increased our understanding of the mutation spectrum and founder effects affecting the PTS gene in East-Asian populations. 6 The patients were from 176 families (Han Chinese populations: 156 families, Japanese: 6 families, South Korean: 7 families, Thai: 3 families and Filipinos: 4 families) and total of 352 mutations were analyzed. Mutations found in these patients were strongly linked to a microsatellite marker, D11S1347.…”