Mutations in the Gene Encoding Gap Junction Protein α12 (Connexin 46

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Mutations in the Gene Encoding Gap Junction Protein α12 (Connexin 46 Mutations in the Gene Encoding Gap Junction Protein α12 (Connexin 46.6) Cause Pelizaeus-Merzbacher–Like Disease Birgit Uhlenberg, Markus Schuelke, Franz Rüschendorf, Nico Ruf, Angela M. Kaindl, Marco Henneke, Holger Thiele, Gisela Stoltenburg- Didinger, Fuat Aksu, Haluk Topaloğlu, Peter Nürnberg, Christoph Hübner, Bernhard Weschke, Jutta Gärtner The American Journal of Human Genetics Volume 75, Issue 2, Pages 251-260 (August 2004) DOI: 10.1086/422763 Copyright © 2004 The American Society of Human Genetics Terms and Conditions

Figure 1 Axial T2-weighted magnetic resonance images of the brain at the level of the basal ganglia. A, Patient with PMLD at 6 years of age (patient III:3; fig. 3). B, Patient with PMD at 7 years of age. The patients in panels A and B show nearly identical hypomyelination patterns of central white matter, as indicated by diffusely enhanced signal intensity. C, Low signal of normal myelination in an unaffected child. The American Journal of Human Genetics 2004 75, 251-260DOI: (10.1086/422763) Copyright © 2004 The American Society of Human Genetics Terms and Conditions

Figure 2 Domains of the GJA12 gene product. Blackened circles depict the locations of mutations. The missense mutations lie within the second (P90S) and fourth (Y272D) transmembrane and third cytoplasmic (M286T) domains. The American Journal of Human Genetics 2004 75, 251-260DOI: (10.1086/422763) Copyright © 2004 The American Society of Human Genetics Terms and Conditions

Figure 3 Haplotypes in family 1 with PMLD. Haplotype analysis indicated that the cosegregating segment of the PMLD locus is flanked proximally by marker rs3902857 and distally by marker rs1321257 on chromosome 1q41-q42. The American Journal of Human Genetics 2004 75, 251-260DOI: (10.1086/422763) Copyright © 2004 The American Society of Human Genetics Terms and Conditions

Figure 4 Segregation of GJA12 mutations (RFLP analysis). In family 2 (f2), the affected boy was compound heterozygous, carrying the paternal c.268C→T missense mutation and the maternal c.989delC frameshift deletion. In family 3 (f3), the affected boy carried the paternal c.718C→T nonsense mutation and the maternal c.814T→G missense mutation. Family numbers correspond to those in table 1. co = control; f1–f3 = families 1–3; mut = mutated GJA12; wt = wild-type GJA12. The American Journal of Human Genetics 2004 75, 251-260DOI: (10.1086/422763) Copyright © 2004 The American Society of Human Genetics Terms and Conditions

Figure 5 Alignment of selected regions of human GJA12 with orthologs of other species, including the Japanese pufferfish Fugu rubripes. Arrows indicate positions of the missense and nonsense mutations in patients with PMLD. Family numbers correspond to those in table 1. f1–f3 = families 1–3. The American Journal of Human Genetics 2004 75, 251-260DOI: (10.1086/422763) Copyright © 2004 The American Society of Human Genetics Terms and Conditions

Figure 6 PCR products of GJA12 and GJB1 cDNA after various numbers of PCR cycles in human brain, spinal cord, sciatic and sural nerve, and skeletal muscle. GJA12 and GJB1 are more highly expressed in brain and spinal cord than in peripheral nerve tissue. Untranscribed RNA was used as a control (co). The American Journal of Human Genetics 2004 75, 251-260DOI: (10.1086/422763) Copyright © 2004 The American Society of Human Genetics Terms and Conditions

Figure A1 Genome scan using the GeneChip Mapping EA 10K Array (Affymetrix). Vertical bars separate the chromosomes. The scanning revealed linkage of PMLD to SNPs on chromosome 1q41-q42. Multipoint linkage analysis yielded a maximum LOD score of 4.83 for SNP markers rs1563353–rs544528. The American Journal of Human Genetics 2004 75, 251-260DOI: (10.1086/422763) Copyright © 2004 The American Society of Human Genetics Terms and Conditions