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. 2000 Sep;67(3):664-71.
doi: 10.1086/303053. Epub 2000 Jul 27.

A novel locus for autosomal recessive peripheral neuropathy in the EGR2 region on 10q23

T Rogers  1 , D Chandler, D Angelicheva, P K Thomas, B Youl, I Tournev, V Gergelcheva, L Kalaydjieva
Affiliations

A novel locus for autosomal recessive peripheral neuropathy in the EGR2 region on 10q23

T Rogers et al. Am J Hum Genet. 2000 Sep.

Abstract

During our studies of Romany (Gypsy) families with hereditary motor and sensory neuropathy-Lom, we have identified a large kindred with two independently segregating autosomal recessive neuropathies. The novel disorder, named "hereditary motor and sensory neuropathy-Russe" (HMSNR), presented as a severe disabling form of Charcot-Marie-Tooth disease with prominent sensory loss, moderately reduced motor nerve conduction velocity, and a high threshold for electrical nerve stimulation. A genome scan in two branches of the large kindred detected linkage to the 10q22-q23 region containing the early growth response 2 gene (EGR2), a transcription factor with a key role in peripheral nerve myelination. The results of sequence analysis and the detection of an intragenic polymorphism allowed us to exclude EGR2 as the HMSNR gene. Further analysis done using linkage and recombination mapping refined the position of the HMSNR gene to a small interval on 10q23.2, flanked by markers D10S581 and D10S1742, telomeric to EGR2. In this interval, a conserved seven-marker haplotype is shared by all disease chromosomes, suggesting a single founder mutation. The homozygosity region is contained in bacterial-artificial-chromosome contig 1570 of the Sanger Centre physical map and has an estimated physical size of approximately 500 kb.

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Figures

Figure 1
Figure 1
Extended pedigree in which HMSNR was identified. Blackened symbols denote subjects affected by HMSNR; symbols containing a vertical line denote subjects affected by HMSNL, which is the other neuropathy in this kindred.
Figure 2
Figure 2
Haplotypes in the region of linkage on 10q22-q23. Marker order is according to the Sanger Centre physical map. For the SNP at nucleotide 1219 of the EGR2 gene, “1” denotes the A allele and “2” denotes the C allele. A, First pedigree used in the genome scan and linkage analysis. For individual R-23, the asterisk (*) denotes a microsatellite mutation, in D10S589, that is assumed to be present on the basis of the conserved flanking haplotypes. B, Second pedigree used in the genome scan and linkage analysis. Different alleles of EGR2 were found to segregate in the two affected branches. Maternal recombination in individual R-11 places the centromeric boundary at D10S581. C, Affected siblings included in the analysis of the 10q22-q23 region. A recombination event in individual R-17 defines marker D10S537 as the telomeric boundary of the HMSNR-gene region.
Figure 3
Figure 3
Marker haplotypes in the 5.2-cM interval (D10S581–D10S537) defined by linkage analysis. Markers D10S561 and EGR2 are included to show the position of EGR2. Marker order is according to the Sanger Centre physical map. Haplotype and EGR2 allele designations are the same as those used in figure 2. Haplotypes N and M are products of the recent recombinations in individuals R-11 and R-17. The two affected members of the large kindred, who were not included in the linkage study, displayed haplotypes D/K and H/J. The unblackened area indicates the assumed ancestral haplotype. Historical recombinations place the HMSNR gene between markers D10S581 and D10S1742.
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References

Electronic-Database Information

    1. GenBank, http://www.ncbi.nlm.nih.gov/Genbank (for EGR2 mRNA [accession numbers J04076 and AF139463])
    1. Genetic Location Database, The, http://cedar.genetics.soton.ac.uk/public_html/ldb.html (for marker D10S2480 from the Southampton map)
    1. Généthon, http://www.genethon.fr/genethon_en.html (for markers for mapping of the candidate area)
    1. Lupski Lab Homepage, http://imgen.bcm.tmc.edu/molgen/lupski/EGR2.html (for EGR2 exon primers and amplification conditions)
    1. Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim/ (for CCFDN [MIM 604168], CMT4A [MIM 214400], CMT4B [MIM 601382], CMT4C [MIM 601596], congenital glaucoma [MIM 231300], congenital myasthenia [MIM 254210], EGR2 [MIM 129010], HMSNL [MIM 601455], and LGMD2C [MIM 253700])

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