Molecular genetics of tetrahydrobiopterin (BH4) deficiency in the Maltese population

Abstract

DeWcient activity of the Dihydropteridine Reductase enzyme (DHPR; EC 1.5.1.34; OMIM 261630) is due to mutations in the Quinoid Dihydropteridine Reductase gene on 4p15.3 (QDPR; RefSeq NM_000320). It results in defective recycling of tetrahydrobiopterin (BH4) and homozygotes have a rare form of atypical Hyperphenylalaninaemia and Phenylketonuria (aPKU). The heterozygote frequency in the Maltese population is high at 3.3%. The more recently described and rarer type of BH4 deWciency due to Sepiapterin Reductase enzyme deWciency (SR; EC 1.1.1.153; OMIM 182125), which presents as an atypical form of Dopa Responsive Dystonia (DRD) [L. Bonafe, B. Thony, J.M. Penzien, B. Czarnecki, N. Blau, Mutations in the sepiapterin reductase gene cause a novel tetrahydrobiopterin-dependent monoamine-neurotransmitter deWciency without hyperphenylalaninemia, Am. J. Hum. Genet. 69 (2001) 269–277; B.R.G. Neville, R. Parascandalo, S. Attard Montalto, R. Farrugia, A.E. Felice, A congenital dopa responsive motor disorder: a Maltese variant due to sepiapterin reductase deWciency, Brain 128 (Pt10) (2005) 2291–2296.] has also been identiWed at high frequency (4.6%) in this population. Two mutations, the c.68G> A in QDPR (p.G23D), and the new SPR, IVS2-2A>G mutation at the splice site consensus sequence in intron 2 of the Sepiapterin Reductase gene (SPR; RefSeq NM_003124) on 2p14–p12, were found to be the sole causative mutations in all the patients with DHPR deWciency and SR deWciency studied. All parents were heterozygotes for the corresponding mutation and showed no clinical symptoms. Three polymorphisms, c.96C > T (p.A32A), c. 345G>A (p.S115S) and c. 396G>A (p.L132L), have also been identiWed in the QDPR gene, deWning four wild-type frameworks, useful in molecular epidemiology studies. The c. 68G>A mutation in QDPR was found only on framework I, suggesting a founder eVect. In contrast no additional sequence diversity was found in the SPR gene whether in wild-type or mutant alleles which is also consistent with a founder eVect. © 2006 Elsevier Inc. All rights reserved.