Molecular Analysis of 55 Spanish Patients with Acute Intermittent Porphyria

Abstract

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.

Characterisation of a common hotspot variant in acute intermittent porphyria sheds light on the mechanism of hydroxymethylbilane synthase function

“…1B) results in a diseaseassociated variant (c.77G>A; p.R26H), which has been described in several different AIP families [36,37]. Two other missense substitutions at the same location, p.R26C and p.R26L, have also been reported [38][39][40][41][42][43][44][45]. In this work, we have sought to characterise the p.R26H variant to shed light on Arg26 and its role in the elongation mechanism of HMBS.…”

Identification and molecular analysis of 17 novel hydroxymethylbilane synthase mutations in 69 Chinese patients with acute intermittent porphyria

“…As of February 2020, a total of 517 HMBS gene mutations were reported, and 2 novel mutations were separately reported by Yang J in April 2020 and by Yang Y in July 2020 [7,8]. In addition, María-José Morán-Jiménez investigated the molecular defects in 55 unrelated Spanish patients with AIP, identifying 6 novel mutations [9]. With the addition of 17 new mutations from this study, the number of HMBS mutations has increased to 542.…”

Identification and molecular analysis of 17 novel variants of hydroxymethylbilane synthase in Chinese patients with acute intermittent porphyria

“…To date, a total of 517 HMBS variants have been reported in the HGMD (version 2020.v2). Our study reports 17 novel variants to the existing literature, increasing the number of HMBS variants to 542 counting 8 novel variants not included in HGMD 14–16 …”