Promoter mutation is a common variant in GJC2-associated Pelizaeus–Merzbacher-like disease E. Meyer a, 1 , M.A. Kurian a, b, 1 , N.V. Morgan a , A. McNeill a , S. Pasha a , L. Tee a , R. Younis a , A. Norman c , M.S. van der Knaap d , E. Wassmer b , R.C. Trembath e , L. Brueton c , E.R. Maher a, c, ⁎ a Department of Medical and Molecular Genetics, Institute of Biomedical Research, Centre for Rare Diseases and Personalised Medicine, University of Birmingham, Birmingham, UK b Department of Paediatric Neurology, Birmingham Children's Hospital, Birmingham, UK c West Midlands Region Genetics Service, Birmingham Women's Hospital NHS Foundation Trust, Birmingham, UK d Department of Child Neurology, VU University Medical Center, Amsterdam, The Netherlands e Department of Medical and Molecular Genetics, King's College London, School of Medicine, Guy's Hospital, London, UK abstract article info Article history: Received 2 August 2011 Received in revised form 30 August 2011 Accepted 30 August 2011 Available online 8 September 2011 Keywords: Neurogenetics Pelizaeus–Merzbacher-like disease (PMLD) is a clinically and genetically heterogeneous neurological disorder of cerebral hypomyelination. It is clinically characterised by early onset (usually infantile) nystagmus, im- paired motor development, ataxia, choreoathetoid movements, dysarthria and progressive limb spasticity. We undertook autozygosity mapping studies in a large consanguineous family of Pakistani origin in which affected children had progressive lower limb spasticity and features of cerebral hypomyelination on MR brain imaging. SNP microarray and microsatellite marker analysis demonstrated linkage to chromosome 1q42.13–1q42.2. Direct sequencing of the gap junction protein gamma-2 gene, GJC2, identified a promoter region mutation (c.-167ANG) in the non-coding exon 1. The c.-167ANG promoter mutation was identified in a further 4 individuals from two families (who were also of Pakistani origin) with clinical and radiological features of PMLD in whom previous routine diagnostic screening of GJC2 had been reported as negative. A common haplotype was identified at the GJC2 locus in the three mutation-positive families, consistent with a common origin for the mutation and likely founder effect. This promoter mutation has only recently been reported in GJC2-PMLD but it has been postulated to affect the binding of the transcription factor SOX10 and appears to be a prevalent mutation, accounting for ~29% of reported patients with GJC2-PMLD. We propose that diagnostic screening of GJC2 should include sequence analysis of the non-coding exon 1, as well as the coding regions to avoid misdiagnosis or diagnostic delay in suspected PMLD. © 2011 Elsevier Inc. All rights reserved. 1. Introduction The hypomyelinating leukoencephalopathies are a clinically and ge- netically heterogeneous group of disorders that are characterised by ab- normal myelin formation in the central nervous system (CNS). The prototypic example is X-linked Pelizaeus–Merzbacher disease (PMD [MIM 312080]) which is caused by mutations in the proteolipid protein gene, PLP1 (MIM 300401) [1] and encodes the major component of my- elin in the CNS [2]. Patients clinically present with nystagmus, impaired motor development, ataxia, a movement disorder (chorea, athetosis), dysarthria, progressive spasticity and diffuse white matter changes on MRI. More recently, a subgroup of patients with clinical and radiological features of PMD who are PLP1-negative have been described. The term Pelizaeus–Merzbacher-like disease (PMLD) has been coined to describe these patients. To date, PMLD appears to be inherited in an autosomal re- cessive manner and mutations have been identified in the gap junction protein gamma-2 gene, GJC2, (MIM 608803, previously known as gap junction protein alpha-12 (GJA12) or connexin 47) [3,4], AIMP1/p43 (MIM 603605) [5] and HSPD1 (MIM 118190) [6]. Here we report nine patients from three PMLD families of Paki- stani origin in which a common GJC2 promoter mutation was detected. Our data implicates a founder effect in these Pakistani PMLD families and provides evidence that this promoter mutation represents a frequent variant in GJC2-associated PMLD. 2. Materials and methods 2.1. Patients Three consanguineous families of Pakistani origin (Families 1–3) were ascertained and recruited for molecular genetic analysis. All Molecular Genetics and Metabolism 104 (2011) 637–643 ⁎ Corresponding author at: Department of Medical and Molecular Genetics, Institute of Biomedical Research, Centre for Rare Diseases and Personalised Medicine, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK. Fax: +44 121 627 2618. E-mail address: E.R.Maher@bham.ac.uk (E.R. Maher). 1 These authors contributed equally to the manuscript and current address: Neuro- sciences Unit, UCL-Institute of Child Health, London. 1096-7192/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.ymgme.2011.08.032 Contents lists available at SciVerse ScienceDirect Molecular Genetics and Metabolism journal homepage: www.elsevier.com/locate/ymgme