Mutations in the gene encoding gap junction protein alpha 12 (connexin 46.6) cause Pelizaeus-Merzbacher-like disease

The hypomyelinating leukodystrophies X-linked Pelizaeus-Merzbacher disease (PMD) and Pelizaeus-Merzbacher-like disease (PMLD) are characterized by nystagmus, progressive spasticity, and ataxia. In a consanguineous family with PMLD, we performed a genomewide linkage scan using the GeneChip Mapping EA...

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Bibliographic Details
Published in:American journal of human genetics 2004-08, Vol.75 (2), p.251-260
Main Authors: Uhlenberg, Birgit, Schuelke, Markus, Rüschendorf, Franz, Ruf, Nico, Kaindl, Angela M, Henneke, Marco, Thiele, Holger, Stoltenburg-Didinger, Gisela, Aksu, Fuat, Topaloğlu, Haluk, Nürnberg, Peter, Hübner, Christoph, Weschke, Bernhard, Gärtner, Jutta
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Connexins - genetics
Female
Haplotypes
Humans
Male
Molecular Sequence Data
Nervous System - metabolism
Nervous System - physiopathology
Pedigree
Pelizaeus-Merzbacher Disease - genetics
Pelizaeus-Merzbacher Disease - metabolism
Pelizaeus-Merzbacher Disease - physiopathology
Protein Structure, Secondary
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Summary:The hypomyelinating leukodystrophies X-linked Pelizaeus-Merzbacher disease (PMD) and Pelizaeus-Merzbacher-like disease (PMLD) are characterized by nystagmus, progressive spasticity, and ataxia. In a consanguineous family with PMLD, we performed a genomewide linkage scan using the GeneChip Mapping EA 10K Array (Affymetrix) and detected a single gene locus on chromosome 1q41-q42. This region harbors the GJA12 gene, which encodes gap junction protein alpha 12 (or connexin 46.6). Gap junction proteins assemble into intercellular channels through which signaling ions and small molecules are exchanged. GJA12 is highly expressed in oligodendrocytes, and, therefore, it serves as an excellent candidate for hypomyelination in PMLD. In three of six families with PMLD, we detected five different GJA12 mutations, including missense, nonsense, and frameshift mutations. We thereby confirm previous assumptions that PMLD is genetically heterogeneous. Although the murine Gja12 ortholog is not expressed in sciatic nerve, we did detect GJA12 transcripts in human sciatic and sural nerve tissue by reverse-transcriptase polymerase chain reaction. These results are in accordance with the electrophysiological finding of reduced motor and sensory nerve conduction velocities in patients with PMLD, which argues for a demyelinating neuropathy. In this study, we demonstrate that GJA12 plays a key role in central myelination and is involved in peripheral myelination in humans.
ISSN:0002-9297
1537-6605
DOI:10.1086/422763