Brief Communication A homozygous tyrosine hydroxylase gene promoter mutation in a patient with dopa-responsive encephalopathy: Clinical, biochemical and genetic analysis Marta Ribase ´s a,1 , Mercedes Serrano b,c,1 , Emilio Ferna ´ndez-A ´ lvarez b,c , Sandra Pahisa d , Aida Ormazabal c,e ,A ´ ngels Garcı ´a-Cazorla b,c , Bele ´n Pe ´rez-Duen ˜as b,c , Jaume Campistol b,c , Rafael Artuch c,e , Bru Cormand c,d,f, * a Departament de Psiquiatria, Hospital Universitari Vall d’Hebron, Barcelona, Spain b Pediatric Neurology Department, Hospital Sant Joan de De ´u, Barcelona, Spain c Centre for Biomedical Research on Rare Diseases (CIBERER), Barcelona, Spain d Departament de Gene `tica, Universitat de Barcelona, Barcelona, Spain e Clinical Biochemistry Department, Hospital Sant Joan de De ´u, Barcelona, Spain f Institut de Biomedicina de la Universitat de Barcelona (IBUB), Spain Received 25 April 2007; received in revised form 6 July 2007; accepted 6 July 2007 Available online 14 August 2007 Abstract We report a recessive mutation in the tyrosine hydroxylase gene (TH) promoter (c.1À71C>T), present at homozygosity in a patient with dopa-responsive encephalopathy. The change lies in a cAMP response element (CRE) and alters a binding site for the CREM tran- scription factor. Previous studies support that the CRE in the TH gene is essential for its transcription, suggesting that mutations within this consensus motif may cause an impairment of catecholamine biosynthesis and lead to a pathogenic phenotype. Ó 2007 Elsevier Inc. All rights reserved. Keywords: Tyrosine hydroxylase deficiency; Dopa-responsive encephalopathy; TH gene promoter; Mutation analysis; cAMP response element; CRE; Neurotransmission Tyrosine hydroxylase (TH, EC 1.14.16.2) catalyses the hydroxylation of L-tyrosine to 3,4-dihydroxyphenylalanine (L-dopa) and is the rate-limiting enzyme in the biosynthesis of the catecholamines dopamine, norepinephrine and epi- nephrine [1]. The human TH gene maps to 11p15.5, contains 14 exons and produces, at least, eight different mRNAs and protein products through alternative splicing and the differential usage of distinct transcription initiation sites [2–4]. In addi- tion, TH levels, stability and activity are highly regulated by different posttranslational mechanisms that include phosphorylation, feedback inhibition by catecholamines, allosteric modulation of the enzyme activity and transla- tional control [5]. Mutations in the TH coding region and splice sites have been associated with decreased enzymatic activity, deter- mine TH deficiency and lead to a variety of clinical pheno- types including a recessive form of Segawa’s syndrome [6], autosomal recessive L-dopa-responsive parkinsonism [7], recessive L-dopa-responsive dystonia (DRD) [8–11], L-dopa non-responsive dystonia or progressive early-onset enceph- alopathy [12]. Fourteen missense mutations, two deletions and one splice site mutation have been identified in the TH gene to date (Fig. 1). The diagnosis of TH deficiency requires the quantifica- tion of biogenic amines and pterins in cerebrospinal fluid 1096-7192/$ - see front matter Ó 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.ymgme.2007.07.004 * Corresponding author. Address: Departament de Gene `tica, Facultat de Biologia, Universitat de Barcelona, Av. Diagonal 645, edifici annex, 3ª planta, 08028 Barcelona, Spain. Fax: +34 934034420. E-mail address: bcormand@ub.edu (B. Cormand). 1 These authors contributed equally to this paper. www.elsevier.com/locate/ymgme Molecular Genetics and Metabolism 92 (2007) 274–277