Mutation hotspots in the human porphobilinogen deaminase gene: Recurrent mutations G111R and R173Q occurring at CpG motifs

Abstract

Acute intermittent porphyria (AIP) is an inherited disorder in the haem biosynthetic pathway caused by a partial deficiency of porphobilinogen (PBG) deaminase. To date, more than 200 different mutations have been identified in the PBG deaminase gene (PBGD) in AIP patients from various countries and ethnic groups. While the majority of the PBGD gene mutations, including most of the mutations occurring at CpG dinucleotides, are family-specific, a few CpG mutations have been observed in a number of AIP patients of European origin. To study the origin of these common CpG mutations, eight intragenic single-nucleotide polymorphisms (SNPs) in the PBGD gene, as well as eight microsatellites flanking the gene in chromosome 11 were used to construct haplotypes in six AIP families of German, Polish and Swiss origins who carried either G111R (4707G>A) or R173Q (6391G>A) mutations. Among the three R173Q families, three distinct haplotypes were found to be cosegregated with the mutation. One Swiss and one German G111R family shared partially an intragenic and its extended microsatellite haplotype, whereas the Polish G111R family showed a unique haplotype. These results indicated that the recurrent CpG mutations that exist in the European AIP population can be either of ancestral origins or derived from de novo events.

The identification of a recurrent phosphoglycerate kinase mutation associated with chronic haemolytic anaemia and neurological dysfunction in a family from USA

“…The same mutation arising repeatedly has been previously described (Vulliamy et al , 1998; Yue et al , 2005). A repeated mutation at a mutational hotspot, such as a CpG site, is usually responsible for this phenomenon (Perry & Carrell, 1989; Schneider‐Yin et al , 2004; Suzuki et al , 2005). However, the nucleotide change that causes the D164V mutation ( c. 491A → T) does not occur in a known mutational hotspot sequence context.…”

Biallelic inactivation of protoporphyrinogen oxidase and hydroxymethylbilane synthase is associated with liver cancer in acute porphyrias

“…This notion was supported by our immunohistochemical findings, which showed a strong reduction in PPOX expression in the HCC tissue of the VP patient. The p.G111R mutation has been identified in AIP patients from a number of countries, including Switzerland [13]. Individuals carrying p.G111R in the heterozygous state show a residual HMBS activity of around 50% of the normal value, indicative of the deleterious effect of this missense mutation on enzyme function.…”

Acute Intermittent Porphyria

“…Our patient had the R173Q missense mutation of HMBS gene, which has been reported in other literatures. [ 4 5 ] For the therapy of AIP, the patients should be treated with a high carbohydrate intake (at least 300 g/d), especially when the patient is fasting. Patients with nausea and/or vomiting will need to receive dextrose with sodium and potassium intravenously, and fluid requirement will vary from patient to patient.…”