doi: 10.1046/j.1529-8817.2003.00114.x SHORT COMMUNICATION Novel HMBS Founder Mutation and Significant Intronic Polymorphism in Spanish Patients with Acute Intermittent Porphyria E. Guill ´ en-Navarro 1 , P. Carbonell 2 , G. Glover 2 , M. S ´ anchez-Sol´ ıs 3 and A. Fern ´ andez-Barreiro 4 1 Unidad de Gen´ etica M´ edica del Servicio de Pediatr´ ıa 2 Unidad de Gen´ etica Molecular del Centro de Bioqu´ ımica y Gen´ etica Cl´ ınica 3 Servicio de Pediatr´ ıa 4 Servicio de Neurolog´ ıa, Hospital Universitario Virgen de la Arrixaca, Murcia, Spain Summary Acute intermittent porphyria (AIP) is an autosomal dominant disorder of heme biosynthesis, caused by a partial deficiency of hydroxymethylbilane synthase (HMBS). Knowledge of the nature of the HMBS mutations causing AIP in Spanish families is very limited. Here we report a novel 669 698del of the HMBS gene in twenty-two individuals from five independent Spanish AIP families, settled in Murcia (southeastern region of Spain). All mutation carriers shared a common disease associated haplotype indicating an ancestral founder effect. Identification of the 669 698del founder mutation allowed rapid and simple molecular diagnosis of AIP in families from this region in Spain. In addition, 771 + 58C>T in intron 12 on the non-669 698del allele was identified in six AIP patients, which promoted homozygous AIP misdiagnosis. Keywords: Acute Intermittent Porphyria; AIP; Hydroxymethylbilane synthase; HMBS; Porphobilinogen deaminase; PBGD; Spanish AIP patients; Founder mutation; Polymorphism Introduction Acute intermittent porphyria (AIP, MIM # 176000) is an autosomal dominant disease caused by a partial de- ficiency of hydroxymethylbilane synthase (HMBS; EC 4.3.1.8). It is characterized by acute attacks of neuro- visceral dysfunction, often precipitated by factors such us hormonal changes, drugs and alcohol. Early detec- tion of AIP carriers is very important for the preven- tion of acute attacks. The diagnosis of AIP is based on clinical symptoms and increased urinary porphyrin precursors, δ-aminolevulinic acid (ALA) and porpho- bilinogen (PBG), in combination with the HMBS activity assay (Kappas et al. 1995). However, the ex- cretion of ALA and PBG may be within the refer- ∗ Correspondence to: Encarna Guill´ en-Navarro, Unidad de Gen´ etica M´ edica, Servicio de Pediatr´ ıa, Hospital Universitario Virgen de la Arrixaca, Ctra. Madrid-Cartagena, s/n, El Pal- mar 30120, Murcia, Spain; Tel.: +34 968369612; Fax: +34 968369681; E-mail: encarna.guillen@carm.es ence range between attacks, and there is an overlapping zone in erythrocyte HMBS activity between affected patients and normal individuals (McColl et al. 1982). Therefore, the diagnosis by molecular technology is crucial. The HMBS gene, located on chromosome 11q23.3 (Jones et al. 1994), comprises 15 exons and two dis- tinct tissue-specific promoters that generate housekeep- ing and erythroid transcripts by alternative splicing (Grandchamp et al. 1987). To date, over 170 different mutations have been identified in the HMBS gene. Most of them are “private,” restricted to only one or a few unrelated AIP patients, but prevalent mutations have also been identified in few populations such as Swe- den (Lee & Anvret, 1991), the Netherlands (Gu et al. 1993), Canada (Greene-Davies et al. 1997), Argentina (De Siervi et al. 1999) and Switzerland (Schneider-Yin et al. 2002), suggesting a “founder effect”. In this study, we report the first founder HMBS gene mutation in Spanish AIP patients, as well as a C  University College London 2004 Annals of Human Genetics (2004) 68,509–514 509