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https://hdl.handle.net/2440/7346
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Type: | Journal article |
Title: | New mutations in MID1 provide support for loss of function as the cause of X-linked Optiz syndrome |
Author: | Cox, T. Allen, L. Cox, L. Hopwood, B. Goodwin, B. Haan, E. Suthers, G. |
Citation: | Human Molecular Genetics, 2000; 9(17):2553-2562 |
Publisher: | Oxford Univ Press |
Issue Date: | 2000 |
ISSN: | 0964-6906 1460-2083 |
Organisation: | Centre for the Molecular Genetics of Development |
Statement of Responsibility: | Timothy C. Cox, Lillian R. Allen, Liza L. Cox, Blair Hopwood, Bruce Goodwin, Eric Haan and Graeme K. Suthers |
Abstract: | Opitz syndrome (OS) is a genetically heterogeneous malformation disorder. Patients with OS may present with a variable array of malformations that are indicative of a disturbance of the primary midline developmental field. Mutations in the C-terminal half of MID1, an RBCC (RING, B-box and coiled-coil) protein, have recently been shown to underlie the X-linked form of OS. Here we show that the MID1 gene spans at least 400 kb, almost twice the distance originally reported and has a minimum of six mRNA isoforms as a result of the alternative use of 5' untranslated exons. In addition, our detailed mutational analysis of MID1 in a cohort of 15 patients with OS has resulted in the identification of seven novel mutations, two of which disrupt the N-terminus of the protein. The most severe of these (E115X) is predicted to truncate the protein before the B-box motifs. In a separate patient, a missense change (L626P) was found that also represents the most C-terminal alteration reported to date. As noted with other C-terminal mutations, GFP fusion constructs demonstrated that the L626P mutant formed cytoplasmic clumps in contrast to the microtubular distribution seen with the wild-type sequence. Notably, however, both N-terminal mutants showed no evidence of cytoplasmic aggregation, inferring that this feature is not pathognomonic for X-linked OS. These new data and the finding of linkage to MID1 in the absence of a demonstrable open reading frame mutation in a further family support the conclusion that X-linked OS results from loss of function of MID1. |
Keywords: | X Chromosome Cell Nucleus Cytoplasm Microtubules Humans Abnormalities, Multiple Syndrome Microtubule Proteins Ubiquitin-Protein Ligases Nuclear Proteins Recombinant Fusion Proteins Transcription Factors DNA, Complementary Codon, Nonsense Pedigree Amino Acid Motifs Zinc Fingers Mutation Mutation, Missense Open Reading Frames Exons Female Male Genetic Linkage |
Description: | Copyright © 2000 Oxford University Press |
DOI: | 10.1093/hmg/9.17.2553 |
Published version: | http://hmg.oxfordjournals.org/cgi/content/full/9/17/2553 |
Appears in Collections: | Aurora harvest 5 Centre for the Molecular Genetics of Development publications Paediatrics publications |
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