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          Institute: MPI für molekulare Genetik     Collection: Department of Human Molecular Genetics     Display Documents

ID: 307435.0, MPI für molekulare Genetik / Department of Human Molecular Genetics
Exonic microdeletions in the X-linked PQBP1 gene in mentally retarded patients: a pathogenic mutation and in-frame deletions of uncertain effect
Authors:Cossée, Mireille; Demeer, Bénédicte; Blanchet, Patricia; Echenne, Bernard; Singh, Deepika; Hagens, Olivier; Antin, Manuela; Finck, Sonja; Vallee, Louis; Dollfus, Hélène; Hegde, Sridevi; Springell, Kelly; Thelma, B. K .; Woods, Geoffrey; Kalscheuer, Vera M.; Mandel, Jean-Louis
Date of Publication (YYYY-MM-DD):2006-02-22
Title of Journal:European Journal of Human Genetics : the Official Journal of the European Society of Human Genetics
Journal Abbrev.:Eur. J. Hum. Genet.
Issue / Number:4
Start Page:418
End Page:425
Copyright:© 2007 European Society of Human Genetics
Review Status:not specified
Audience:Experts Only
Abstract / Description:Mutations in PQBP1 were recently identified in families with syndromic and non-syndromic X-linked mental retardation (XLMR). Clinical features frequently associated with MR were microcephaly and/or short stature. The predominant mutations detected so far affect a stretch of six AG dinucleotides in the polar-amino-acid-rich domain (PRD), causing frameshifts in the fourth coding exon. We searched for PQBP1 exon 4 frameshifts in 57 mentally retarded males in whom initial referral description indicated at least one of the following criteria: microcephaly, short stature, spastic paraplegia or family history compatible with XLMR, and in 772 mentally retarded males not selected for specific clinical features or family history. We identified a novel frameshift mutation (23 bp deletion) in two half-brothers with specific clinical features, and performed prenatal diagnosis in this family. We also found two different 21 bp in-frame deletions (c.334–354del(21 bp) and c.393–413del(21 bp)) in four unrelated probands from various ethnic origins, each deleting one of five copies of an imperfect seven amino-acid repeat. Although such deletions have not been detected in 1180 X chromosomes from European controls, the c. 334–354del(21 bp) was subsequently found in two of 477 Xs from Indian controls. We conclude that pathogenic frameshift mutations in PQBP1 are rare in mentally retarded patients lacking specific associated signs and that the 21 bp in-frame deletions may be non-pathogenic, or alternatively could act subtly on PQBP1 function. This touches upon a common dilemma in XLMR, that is, how to distinguish between mutations and variants that may be non-pathogenic or represent risk factors for cognitive impairment.
Free Keywords:X-linked MR, PQBP1, mutations
Comment of the Author/Creator:Correspondence: Dr M Cossée, Laboratoire de diagnostic génétique, Hôpitaux Universitaires de Strasbourg, Faculté de Médecine, 11 rue Humann, 67085 Strasbourg Cedex, France. Tel: 00 33 3 90 24 33 40; Fax: 00 33 3 90 24 33 28; E-mail: cossee@igbmc.u-strasbg.fr
External Publication Status:published
Document Type:Article
Version Comment:Automatic journal name synchronization
Communicated by:Hans-Hilger Ropers
Affiliations:MPI für molekulare Genetik
External Affiliations:1.Laboratoire de diagnostic génétique, Hôpitaux Universitaires de Strasbourg et Faculté de Médecine, Strasbourg, France;
2.Service de génétique médicale, CHU de Montpellier, France;
3.Service de neuropédiatrie, CHU de Montpellier, France;
4.Department of Genetics, University of Delhi South Campus, New Delhi, India;
5.Service de Pédiatrie, Hôpital de Haguenau, France;
6.Service de neuropédiatrie, CHU de Lille, France;
7.Service de Génétique Médicale, Hôpitaux Universitaires de Strasbourg, Strasbourg, France;
8.Manipal Hospital, Bangalore, India;
9.Molecular Medicine Unit, St James's University Hospital, Leeds, UK;
10.IGBMC (CNRS/INSERM/ULP) and Collège de France, Illkirch, France.
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