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Open AccessArticle

Molecular Analysis of 55 Spanish Patients with Acute Intermittent Porphyria

1
Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Fundación para la Investigación Biomédica del Hospital 12 de Octubre, Centro de Investigación, Avenida de Córdoba s/n, 28041 Madrid, Spain
2
Servicio de Análisis Clínicos, Hospital 12 de Octubre, 28041 Madrid, Spain
3
Servicio de Medicina Interna, Hospital 12 de Octubre, 28041 Madrid, Spain
*
Author to whom correspondence should be addressed.
Genes 2020, 11(8), 924; https://doi.org/10.3390/genes11080924
Received: 13 July 2020 / Revised: 29 July 2020 / Accepted: 10 August 2020 / Published: 12 August 2020
Acute intermittent porphyria (AIP) results from a decreased activity of hepatic hydroxymethylbilane synthase (HMBS), the third enzyme in the heme biosynthetic pathway. AIP is an autosomal dominant disorder with incomplete penetrance, characterized by acute neurovisceral attacks precipitated by several factors that induce the hepatic 5-aminolevulinic acid synthase, the first enzyme in the heme biosynthesis. Thus, a deficiency in HMBS activity results in an overproduction of porphyrin precursors and the clinical manifestation of the disease. Early diagnosis and counselling are essential to prevent attacks, and mutation analysis is the most accurate method to identify asymptomatic carriers in AIP families. In the present study, we have investigated the molecular defects in 55 unrelated Spanish patients with AIP, identifying 32 HMBS gene mutations, of which six were novel and ten were found in more than one patient. The novel mutations included a missense, an insertion, two deletions, and two splice site variants. Prokaryotic expression studies demonstrated the detrimental effect for the missense mutation, whereas reverse transcription-PCR and sequencing showed aberrant splicing caused by each splice site mutation. These results will allow for an accurate diagnosis of carriers of the disease in these families. Furthermore, they increase the knowledge about the molecular heterogeneity of AIP in Spain. View Full-Text
Keywords: porphyria; acute intermittent porphyria; hydroxymethylbilane synthase; porphobilinogen deaminase; mutation analysis; splicing defect; prokaryotic expression porphyria; acute intermittent porphyria; hydroxymethylbilane synthase; porphobilinogen deaminase; mutation analysis; splicing defect; prokaryotic expression
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Morán-Jiménez, M.-J.; Borrero-Corte, M.-J.; Jara-Rubio, F.; García-Pastor, I.; Díaz-Díaz, S.; Castelbón-Fernandez, F.-J.; Enríquez-de-Salamanca, R.; Méndez, M. Molecular Analysis of 55 Spanish Patients with Acute Intermittent Porphyria. Genes 2020, 11, 924.

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