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A novel mechanism for variable phenotypic expressivity in Mendelian diseases uncovered by an AU-rich element (ARE)-creating mutation.

ABSTRACT: Variable 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.We 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.This 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.

SUBMITTER: Patel N

PROVIDER: S-EPMC5534118 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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A novel mechanism for variable phenotypic expressivity in Mendelian diseases uncovered by an AU-rich element (ARE)-creating mutation.

Patel Nisha N Khan Arif O AO Al-Saif Maher M Moghrabi Walid N WN AlMaarik Balsam M BM Ibrahim Niema N Abdulwahab Firdous F Hashem Mais M Alshidi Tarfa T Alobeid Eman E Alomar Rana A RA Al-Harbi Saad S Abouelhoda Mohamed M Khabar Khalid S A KSA Alkuraya Fowzan S FS

Genome biology 20170728 1

<h4>Background</h4>Variable 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.<h4>Results</h4>We report three consanguineous families in which an isolated ocular phenotype ...[more]

PMID: 28754144

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Project description:The yeast M-NM-6-crystallin Zta1p interacts specifically with RNA sequences rich in adenine and uracil (AU-rich element). We have looked for possible targets of Zta1p through a comparative transcriptional analysis of the yeast defective in ZTA1 (M-NM-^Tzta1) versus the wild-type by microarray. This revealed that a group of genes implicated on amino acid biosynthesis are affected by the lack of ZTA1. The effect on one of the targets ARG4 was studied in more detail, revealing a clear positive correlation between ZTA1 and ARG4 expression at the mRNA level. We demonstrate that Zta1p is able to bind specifically to the 3M-bM-^@M-^YUTR AU-rich elements of ARG4 mRNA in vitro, suggesting that the mechanism by which ZTA1 modulates the expression of ARG4 is probably mediated by this mRNA binding ability. Moreover, the expression of ZTA1 is also under the control of the TOR pathway, and under Gcn4p, which regulates genes implicated in the response to nutrient availability and the general amino acid control (GAAC). In summary, our results shed light on the functional role of the M-NM-6-crystallin family as stress response proteins, with a conserved functional role, from yeast to humans, in the post-transcriptional regulation of genes that need to be rapidly activated for cell defense. Triplicate biological replicate experiments were performed, where the two strains, M-bM-^HM-^Fzta1 and wild-type, were grown in the presence or absence of hydrogen peroxide. The experimental design was defined to directly compare the M-bM-^HM-^Fzta1 versus the wild-type strain in either of the two hydrogen peroxide treatment conditions (i.e. treated M-bM-^HM-^Fzta1 versus treated wt, or untreated M-bM-^HM-^Fzta1 versus untreated wt). A duplicate hybridization on a separate array with dye swapping was performed in each case to correct for dye bias effects. Thus, a total of 12 array data sets were produced as a result of processing three experimental pairs of samples, for each of two treatment conditions, with dye swap duplicates.

Dataset Information

A novel mechanism for variable phenotypic expressivity in Mendelian diseases uncovered by an AU-rich element (ARE)-creating mutation.

Publications

A novel mechanism for variable phenotypic expressivity in Mendelian diseases uncovered by an AU-rich element (ARE)-creating mutation.

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