Allelic Expression Imbalance Promoting a Mutant PEX6 Allele Causes Zellweger Spectrum Disorder

Falkenberg, Kim D.; Braverman, Nancy; Moser, Ann B.; Steinberg, Steven J.; Klouwer, Femke C. C.; Schlüter, Agatha; Ruíz, Montserrat; Pujol, Aurora; Engvall, Martin; Naess, K; Spronsen, F. J. van; Körver‐Keularts, Irene M. L. W.; Rubio-Gozalbo, M. Estela; Ferdinandusse, Sacha; Wanders, Ronald J. A.; Waterham, Hans R.

doi:10.1016/j.ajhg.2017.11.007

Cited by 40 publications

(33 citation statements)

References 37 publications

(45 reference statements)

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“…Except for heterozygosity of the known mutation in the 10 patients, we did not identify novel variants or indications for large deletions, nonsense‐mediated decay or exon skipping. We also did not observe allelic expression imbalance promoting expression of the allele containing the heterozygous mutation, a phenomenon we recently reported as underlying cause for Zellweger spectrum disorder (Falkenberg et al, ). When we next sequenced the 264‐bp‐long 5′UTR sequence of the SLC22A5 gene, we noted that all patients heterozygous for a known mutation were also heterozygous for a GRCh38:5:132369824:G:A; NM_003060.3:c.‐149G>A variant, while two patients, in whom no mutations had been found, were homozygous for this variant.…”

Section: Resultssupporting

confidence: 66%

A mutation creating an upstream translation initiation codon in SLC22A5 5′UTR is a frequent cause of primary carnitine deficiency

et al. 2019

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Primary carnitine deficiency is caused by a defect in the active cellular uptake of carnitine by Na+‐dependent organic cation transporter novel 2 (OCTN2). Genetic diagnostic yield for this metabolic disorder has been relatively low, suggesting that disease‐causing variants are missed. We Sanger sequenced the 5′ untranslated region (UTR) of SLC22A5 in individuals with possible primary carnitine deficiency in whom no or only one mutant allele had been found. We identified a novel 5′‐UTR c.‐149G>A variant which we characterized by expression studies with reporter constructs in HeLa cells and by carnitine‐transport measurements in fibroblasts using a newly developed sensitive assay based on tandem mass spectrometry. This variant, which we identified in 57 of 236 individuals of our cohort, introduces a functional upstream out‐of‐frame translation initiation codon. We show that the codon suppresses translation from the wild‐type ATG of SLC22A5, resulting in reduced OCTN2 protein levels and concomitantly lower transport activity. With an allele frequency of 24.2% the c.‐149G>A variant is the most frequent cause of primary carnitine deficiency in our cohort and may explain other reported cases with an incomplete genetic diagnosis. Individuals carrying this variant should be clinically re‐evaluated and monitored to determine if this variant has clinical consequences.

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Section: Resultssupporting

confidence: 66%

A mutation creating an upstream translation initiation codon in SLC22A5 5′UTR is a frequent cause of primary carnitine deficiency

et al. 2019

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“… Although it is estimated that every individual is a carrier of 10 to 20 loss‐of‐function (LoF) variants with an allelic frequency of <0.5%, it is intriguing that P8 should be a carrier of a LoF variant in a strong candidate gene. Further studies to rule out a tissue‐specific reduction of normal mRNA, an allelic expression imbalance or a second de novo mutational event should also be conducted.…”

Section: Discussionmentioning

confidence: 99%

Clinical and molecular diagnosis of non‐phosphomannomutase 2 N‐linked congenital disorders of glycosylation in Spain

et al. 2019

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The congenital disorders of glycosylation (CDG) are defects in glycoprotein and glycolipid glycan synthesis and attachment. They affect multiple organ/systems, but non‐specific symptoms render the diagnosis of the different CDG very challenging. Phosphomannomutase 2 (PMM2)‐CDG is the most common CDG, but advances in genetic analysis have shown others to occur more commonly than previously thought. The present work reports the clinical and mutational spectrum of 25 non‐PMM2 CDG patients. The most common clinical symptoms were hypotonia (80%), motor or psychomotor disability (80%) and craniofacial dysmorphism (76%). Based on their serum transferrin isoform profile, 18 were classified as CDG‐I and 7 as CDG‐II. Pathogenic variations were found in 16 genes (ALG1, ALG6, ATP6V0A2, B4GALT1, CCDC115, COG7, DOLK, DPAGT1, DPM1, GFPT1, MPI, PGM1, RFT1, SLC35A2, SRD5A3, and SSR4). Overall, 27 variants were identified, 12 of which are novel. The results highlight the importance of combining genetic and biochemical analyses for the early diagnosis of this heterogeneous group of disorders.

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“…In malignant hyperthermia patients, allelic imbalance of the ryanodine receptor gene was determined which might underlie the variable penetrance of the disease [ 38 ]. Allelic imbalance resulting in increased expression of the mutant allele can also lead to onset of a recessive disorder in heterozygous patients, as shown for a causative mutation in Zellweger Spectrum Disorder [ 30 ]. In summary, in several diseases including HCM, the increased expression of the disease-causing allele seems to contribute to severity, pathogenic phenotype and the clinical onset of the respective disorder.…”

Section: Hypotheses On the Pathomechanisms In Hcmmentioning

confidence: 99%

Altered force generation and cell-to-cell contractile imbalance in hypertrophic cardiomyopathy

Kraft

Montag

2019

Pflugers Arch - Eur J Physiol

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Hypertrophic cardiomyopathy (HCM) is mainly caused by mutations in sarcomeric proteins. Thirty to forty percent of identified mutations are found in the ventricular myosin heavy chain (β-MyHC). A common mechanism explaining how numerous mutations in several different proteins induce a similar HCM-phenotype is unclear. It was proposed that HCM-mutations cause hypercontractility, which for some mutations is thought to result from mutation-induced unlocking of myosin heads from a so-called super-relaxed state (SRX). The SRX was suggested to be related to the “interacting head motif,” i.e., pairs of myosin heads folded back onto their S2-region. Here, we address these structural states of myosin in context of earlier work on weak binding cross-bridges. However, not all HCM-mutations cause hypercontractility and/or are involved in the interacting head motif. But most likely, all mutations alter the force generating mechanism, yet in different ways, possibly including inhibition of SRX. Such functional—hyper- and hypocontractile—changes are the basis of our previously proposed concept stating that contractile imbalance due to unequal fractions of mutated and wildtype protein among individual cardiomyocytes over time will induce cardiomyocyte disarray and fibrosis, hallmarks of HCM. Studying β-MyHC-mutations, we found substantial contractile variability from cardiomyocyte to cardiomyocyte within a patient’s myocardium, much higher than in controls. This was paralleled by a similarly variable fraction of mutant MYH7 -mRNA (cell-to-cell allelic imbalance), due to random, burst-like transcription, independent for mutant and wildtype MYH7 -alleles. Evidence suggests that HCM-mutations in other sarcomeric proteins follow the same disease mechanism.

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Allelic Expression Imbalance Promoting a Mutant PEX6 Allele Causes Zellweger Spectrum Disorder

Cited by 40 publications

References 37 publications

A mutation creating an upstream translation initiation codon in SLC22A5 5′UTR is a frequent cause of primary carnitine deficiency

A mutation creating an upstream translation initiation codon in SLC22A5 5′UTR is a frequent cause of primary carnitine deficiency

Clinical and molecular diagnosis of non‐phosphomannomutase 2 N‐linked congenital disorders of glycosylation in Spain

Altered force generation and cell-to-cell contractile imbalance in hypertrophic cardiomyopathy

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