ArticleGenome biology2017
A novel mechanism for variable phenotypic expressivity in Mendelian diseases uncovered by an AU-rich element (ARE)-creating mutation.
Article in Genome biology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 28 citations in OpenAlex.
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- Beyond the exome: utility of long-read whole genome sequencing in exome-negative autosomal recessive diseases.Genome medicine · 2023Article
- Constitutive overexpression of cellobiohydrolase 2 inEngineering microbiology · 2023Article
- Heterogeneity in biomarkers, mitogenome and genetic disorders of the Arab population with special emphasis on large-scale whole-exome sequencing.Archives of medical science : AMS · 2023Article
- Post-transcriptional screen of cancer amplified genes identifies ERBB2/Her2 signaling as AU-rich mRNA stability-promoting pathway.Oncogenesis · 2021Article
- Epilepsy, status epilepticus, and hemiplegic migraine coexisting with a novel SLC4A4 mutation.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2021Article
- Kinome inhibition reveals a role for polo-like kinase 1 in targeting post-transcriptional control in cancer.Molecular oncology · 2021Article
- ASHG 2020 Curt Stern Award introduction: Fowzan Sami Alkuraya.American journal of human genetics · 2021Article
- Clinical and functional significance of tumor/stromal ATR expression in breast cancer patients.Breast cancer research : BCR · 2020Article
- Zeta-crystallin: a moonlighting player in cancer.Cellular and molecular life sciences : CMLS · 2020Review
- Congenital glaucoma and CYP1B1: an old story revisited.Human genetics · 2019Article
- SLC4A4 compound heterozygous mutations in exon-intron boundary regions presenting with severe proximal renal tubular acidosis and extrarenal symptoms coexisting with Turner's syndrome: a case report.BMC medical genetics · 2018Article
- Pervasive allele-specific regulation on RNA decay in hybrid mice.Life science alliance · 2018Article
- Mouse models of SLC4-linked disorders of HCOAmerican journal of physiology. Cell physiology · 2018Review
- RNAs: dynamic and mutable.Genome biology · 2017Article
Corrections and comments
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Authors and funding
15 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundVariable expressivity is a well-known phenomenon in which patients with mutations in one gene display varying degrees of clinical severity, potentially displaying only subsets of the clinical manifestations associated with the multisystem disorder linked to the gene. This remains an incompletely understood phenomenon with proposed mechanisms ranging from allele-specific to stochastic.
resultsWe report three consanguineous families in which an isolated ocular phenotype is linked to a novel 3' UTR mutation in SLC4A4, a gene known to be mutated in a syndromic form of intellectual disability with renal and ocular involvement. Although SLC4A4 is normally devoid of AU-rich elements (AREs), a 3' UTR motif that mediates post-transcriptional control of a subset of genes, the mutation we describe creates a functional ARE. We observe a marked reduction in the transcript level of SLC4A4 in patient cells. Experimental confirmation of the ARE-creating mutation is shown using a post-transcriptional reporter system that reveals consistent reduction in the mRNA-half life and reporter activity. Moreover, the neo-ARE binds and responds to the zinc finger protein ZFP36/TTP, an ARE-mRNA decay-promoting protein.
conclusionsThis novel mutational mechanism for a Mendelian disease expands the potential mechanisms that underlie variable phenotypic expressivity in humans to also include 3' UTR mutations with tissue-specific pathology.
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