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ABCB6 polymorphisms are not overly represented in patients with porphyria.

ABSTRACT: The Mendelian inheritance pattern of acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria is autosomal dominant, but the clinical phenotype is heterogeneous. Within the general population, penetrance is low, but among first-degree relatives of a symptomatic proband, penetrance is higher. These observations suggest that genetic factors, in addition to mutation of the specific enzyme of the biosynthetic pathway of heme, contribute to the clinical phenotype. Recent studies by others suggested that the genotype of the transporter protein ABCB6 contribute to the porphyria phenotype. Identifying the molecule(s) that are transported by ABCB6 has been problematic and has led to uncertainty with respect to how or if variants/mutants contribute to phenotypic heterogeneity. Knockout mouse models of Abcb6 have not provided a direction for investigation as homozygous knockout animals do not have a discrete phenotype. To address the proposed link between ABC6 genotype and porphyria phenotype, a large cohort of patients with acute hepatic porphyria and erythropoietic protoporphyria was analyzed. Our studies showed that ABCB6 genotype did not correlate with disease severity. Therefore, genotyping of ABCB6 in patients with acute hepatic porphyria and erythropoietic protoporphyria is not warranted.

SUBMITTER: Farrell CP

PROVIDER: S-EPMC8945301 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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ABCB6 polymorphisms are not overly represented in patients with porphyria.

Farrell Colin P CP Nicolas Gäel G Desnick Robert J RJ Parker Charles J CJ Lamoril Jerome J Gouya Laurent L Karim Zoubida Z Tchernitchko Dimitri D Chan Brenden B Puy Herve H Phillips John D JD

Blood advances 20220201 3

The Mendelian inheritance pattern of acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria is autosomal dominant, but the clinical phenotype is heterogeneous. Within the general population, penetrance is low, but among first-degree relatives of a symptomatic proband, penetrance is higher. These observations suggest that genetic factors, in addition to mutation of the specific enzyme of the biosynthetic pathway of heme, contribute to the clinical phenotype. Recent studi ...[more]

PMID: 34724702

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Project description:BACKGROUND: The search for enriched features has become widely used to characterize a set of genes or proteins. A key aspect of this technique is its ability to identify correlations amongst heterogeneous data such as Gene Ontology annotations, gene expression data and genome location of genes. Despite the rapid growth of available data, very little has been proposed in terms of formalization and optimization. Additionally, current methods mainly ignore the structure of the data which causes results redundancy. For example, when searching for enrichment in GO terms, genes can be annotated with multiple GO terms and should be propagated to the more general terms in the Gene Ontology. Consequently, the gene sets often overlap partially or totally, and this causes the reported enriched GO terms to be both numerous and redundant, hence, overwhelming the researcher with non-pertinent information. This situation is not unique, it arises whenever some hierarchical clustering is performed (e.g. based on the gene expression profiles), the extreme case being when genes that are neighbors on the chromosomes are considered. RESULTS: We present a generic framework to efficiently identify the most pertinent over-represented features in a set of genes. We propose a formal representation of gene sets based on the theory of partially ordered sets (posets), and give a formal definition of target set pertinence. Algorithms and compact representations of target sets are provided for the generation and the evaluation of the pertinent target sets. The relevance of our method is illustrated through the search for enriched GO annotations in the proteins involved in a multiprotein complex. The results obtained demonstrate the gain in terms of pertinence (up to 64% redundancy removed), space requirements (up to 73% less storage) and efficiency (up to 98% less comparisons). CONCLUSION: The generic framework presented in this article provides a formal approach to adequately represent available data and efficiently search for pertinent over-represented features in a set of genes or proteins. The formalism and the pertinence definition can be directly used by most of the methods and tools currently available for feature enrichment analysis.

Project description:BACKGROUND: A partial deficiency in Protoporphyrinogen oxidase (PPOX) produces the mixed disorder Variegate Porphyria (VP), the second acute porphyria more frequent in Argentina. Identification of patients with an overt VP is absolutely important because treatment depends on an accurate diagnosis but more critical is the identification of asymptomatic relatives to avoid acute attacks which may progress to death. METHODS: We have studied at molecular level 18 new Argentinean patients biochemically diagnosed as VP. PPOX gene was amplified in one or in twelve PCR reactions. All coding exons, flanking intronic and promoter regions were manual or automatically sequenced. For RT-PCR studies RNA was retrotranscripted, amplified and sequenced. PPOX activity in those families carrying a new and uncharacterized mutation was performed. RESULTS: All affected individuals harboured mutations in heterozygous state. Nine novel mutations and 3 already reported mutations were identified. Six of the novel mutations were single nucleotide substitutions, 2 were small deletions and one a small insertion. Three single nucleotide substitutions and the insertion were at exon-intron boundaries. Two of the single nucleotide substitutions, c.471G>A and c.807G>A and the insertion (c.388+3insT) were close to the splice donor sites in exons 5, 7 and intron 4 respectively. The other single nucleotide substitution was a transversion in the last base of intron 7, g.3912G>C (c.808-1G>C) so altering the consensus acceptor splice site. However, only in the first case the abnormal band showing the skipping of exon 5 was detected. The other single nucleotide substitutions were transversions: c.101A>T, c.995G>C and c.670 T>G that result in p.E34V, p.G332A and W224G aminoacid substitutions in exons 3, 10 and 7 respectively. Activity measurements indicate that these mutations reduced about 50% PPOX activity and also that they co-segregate with this reduced activity value. Two frameshift mutations, c.133delT and c.925delA, were detected in exons 3 and 9 respectively. The first leads to an early termination signal 22 codons downstream (p.S45fsX67) and the second leads to a stop codon 5 codons downstream (p.I309fsX314). One reported mutation was a missense mutation (p.G232R) and 2 were frameshift mutations: c.1082insC and 1043insT. The last mutation was detected in six new apparently unrelated Argentinean families. CONCLUSION: Molecular analysis in available family members revealed 14 individuals who were silent carriers of VP. Molecular techniques represent the most accurate approach to identify unaffected carriers and to provide accurate genetic counselling for asymptomatic individuals. The initial screening includes the insertion search.

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ABCB6 polymorphisms are not overly represented in patients with porphyria.

Publications

ABCB6 polymorphisms are not overly represented in patients with porphyria.

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