Qualitative and quantitative analysis of the effect of splicing mutations in propionic acidemia underlying non-severe phenotypes

Clavero, Sonia; Pérez, Belén; Rincón, Ana María; Ugarte, Magdalena; Desviat, Lourdes R.

doi:10.1007/s00439-004-1147-1

Cited by 17 publications

(12 citation statements)

References 28 publications

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“…Indeed, as indicated in the results, even if the mutant allele presents novel potential donor splice sites with increased consensus splicing value, the natural site only presents a moderately decreased consensus splicing value and is likely partially used, as previously reported [Kaler et al, 1994;McConville et al, 1996;Møller et al, 2000;Clavero et al, 2004;Cao et al, 2010]. Thus, the haploinsufficiency in this patient would be partial.…”

Section: Discussionmentioning

confidence: 53%

Report of two novel mutations in PTHLH associated with brachydactyly type E and literature review

Thomas‐Teinturier

Pereda

Garin

et al. 2015

American J of Med Genetics Pt A

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Autosomal-dominant brachydactyly type E is a congenital limb malformation characterized by small hands and feet as a result of shortened metacarpals and metatarsals. Alterations that predict haploinsufficiency of PTHLH, the gene coding for parathyroid hormone related protein (PTHrP), have been identified as a cause of this disorder in seven families. Here, we report three patients affected with brachydactyly type E, caused by PTHLH mutations expected to result in haploinsufficiency, and discuss our data compared to published reports.

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Section: Discussionmentioning

confidence: 53%

Report of two novel mutations in PTHLH associated with brachydactyly type E and literature review

Thomas‐Teinturier

Pereda

Garin

et al. 2015

American J of Med Genetics Pt A

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“…Surprisingly, two canonical splice-site mutations showed much lower levels of skipped transcripts (c.5206-2A4G, and c.5546G4A). However, there are similar cases in the literature, such as mutation c.1825-2A4G in one of the genes responsible for propionic acidemia (PCCA; MIM] 232000), where a proportion of correctly spliced transcripts were derived from the mutated allele [Clavero et al, 2004]. In these particular cases it could be speculated that other sequences are also relevant for the correct functioning of the splicing machinery.…”

Section: The Importance Of Mutation In Determining the Nf1-trancriptimentioning

confidence: 92%

NF1mutation rather than individual genetic variability is the main determinant of theNF1-transcriptional profile of mutations affecting splicing

Pros¹,

Larriba²,

López³

et al. 2006

Hum. Mutat.

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A significant number of neurofibromatosis type 1 (NF1) mutations result in exon skipping. The majority of these mutations do not occur in the canonical splice sites and can produce different aberrant transcripts whose proportions have not been well studied. It has been hypothesized that differences in the mutation-determined NF1-transcriptional profile could partially explain disease variability among patients bearing the same NF1 splice defect. In order to gain insight into these aspects, we analyzed the proportion of the different transcripts generated by nine NF1-splicing mutations in 30 patients. We assessed the influence of the mutation in the NF1-related transcriptional profiles and investigated the existence of individual differences in a global manner. We analyzed potential differences in tissue-specific transcriptional profiles and evaluated the influence of sample processing and mRNA nonsense-mediated decay (NMD). Small transcriptional differences were found in neurofibromas and neurofibroma-derived Schwann cells (SC) compared to blood. We also detected a higher cell culture-dependent NMD. We observed that mutation per se explains 93.5% of the profile variability among mutations studied. However, despite the importance of mutation in determining the proportion of NF1 transcripts generated, we found certain variability among patients with the same mutation. From our results, it seems that genetic factors influencing RNA processing play a minor role in determining the NF1-transcriptional profile. Nevertheless neurofibromin studies would clarify whether these small differences translate into significant functional changes that could explain the great clinical expressivity observed in the disease or any of the disease-related traits.

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“…PPA is also known to modulate neurofilament phosphorylation/dephosporylation, important in neurodevelopment and neuroplasticity (137, 138). …”

Section: Potential Underlying Mechanisms Of Ppa and Their Relation Tomentioning

confidence: 99%

Short-chain fatty acid fermentation products of the gut microbiome: implications in autism spectrum disorders

MacFabe¹

2012

Microbial Ecology in Health & Disease

281

352

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Recent evidence suggests potential, but unproven, links between dietary, metabolic, infective, and gastrointestinal factors and the behavioral exacerbations and remissions of autism spectrum disorders (ASDs). Propionic acid (PPA) and its related short-chain fatty acids (SCFAs) are fermentation products of ASD-associated bacteria (Clostridia, Bacteriodetes, Desulfovibrio). SCFAs represent a group of compounds derived from the host microbiome that are plausibly linked to ASDs and can induce widespread effects on gut, brain, and behavior. Intraventricular administration of PPA and SCFAs in rats induces abnormal motor movements, repetitive interests, electrographic changes, cognitive deficits, perseveration, and impaired social interactions. The brain tissue of PPA-treated rats shows a number of ASD-linked neurochemical changes, including innate neuroinflammation, increased oxidative stress, glutathione depletion, and altered phospholipid/acylcarnitine profiles. These directly or indirectly contribute to acquired mitochondrial dysfunction via impairment in carnitine-dependent pathways, consistent with findings in patients with ASDs. Of note, common antibiotics may impair carnitine-dependent processes by altering gut flora favoring PPA-producing bacteria and by directly inhibiting carnitine transport across the gut. Human populations that are partial metabolizers of PPA are more common than previously thought. PPA has further bioactive effects on neurotransmitter systems, intracellular acidification/calcium release, fatty acid metabolism, gap junction gating, immune function, and alteration of gene expression that warrant further exploration. These findings are consistent with the symptoms and proposed underlying mechanisms of ASDs and support the use of PPA infusions in rats as a valid animal model of the condition. Collectively, this offers further support that gut-derived factors, such as dietary or enteric bacterially produced SCFAs, may be plausible environmental agents that can trigger ASDs or ASD-related behaviors and deserve further exploration in basic science, agriculture, and clinical medicine.

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Qualitative and quantitative analysis of the effect of splicing mutations in propionic acidemia underlying non-severe phenotypes

Cited by 17 publications

References 28 publications

Report of two novel mutations in PTHLH associated with brachydactyly type E and literature review

Report of two novel mutations in PTHLH associated with brachydactyly type E and literature review

NF1mutation rather than individual genetic variability is the main determinant of theNF1-transcriptional profile of mutations affecting splicing

Short-chain fatty acid fermentation products of the gut microbiome: implications in autism spectrum disorders

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