1. ¹Laboratoire de diagnostic génétique, Hôpitaux Universitaires de Strasbourg et Faculté de Médecine, Strasbourg, France
2. ²Service de génétique médicale, CHU de Montpellier, France
3. ³Service de neuropédiatrie, CHU de Montpellier, France
4. ⁴Department of Genetics, University of Delhi South Campus, New Delhi, India
5. ⁵Max Planck Institute for Molecular Genetics, Berlin, Germany
6. ⁶Service de Pédiatrie, Hôpital de Haguenau, France
7. ⁷Service de neuropédiatrie, CHU de Lille, France
8. ⁸Service de Génétique Médicale, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
9. ⁹Manipal Hospital, Bangalore, India
10. ¹⁰Molecular Medicine Unit, St James's University Hospital, Leeds, UK
11. ¹¹IGBMC (CNRS/INSERM/ULP) and Collège de France, Illkirch, France

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

¹²These authors contributed equally to this work.

Received 15 August 2005; Revised 22 December 2005; Accepted 22 December 2005; Published online 22 February 2006.

Abstract

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.