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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
Organisation: Centre for the Molecular Genetics of Development
Statement of
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
Abnormalities, Multiple
Microtubule Proteins
Ubiquitin-Protein Ligases
Nuclear Proteins
Recombinant Fusion Proteins
Transcription Factors
DNA, Complementary
Codon, Nonsense
Amino Acid Motifs
Zinc Fingers
Mutation, Missense
Open Reading Frames
Genetic Linkage
Description: Copyright © 2000 Oxford University Press
DOI: 10.1093/hmg/9.17.2553
Published version:
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Centre for the Molecular Genetics of Development publications
Paediatrics publications

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