Localization of a non-specific X-linked mental retardation gene, MRX23, to Xq23-q24
Localization of a non-specific X-linked mental retardation gene, MRX23, to Xq23-q24Ronald G. Gregg*, Christina Palmer1, Susan Kirkpatrick1 and Amy Simantel
Waisman Center for Mental Retardation and Human Development, University of Wisconsin, Madison, WI 53706, USA and 1Department of Medical Genetics and Pediatrics, University of Wisconsin, Madison, WI 53706, USA
Received October 25, 1995;Revised and Accepted January 4, 1996
More than 100 X-linked mental retardation syndromes have been described. We report the localization of the disease gene, MRX23, in one family to Xq23-24. Affected family members present with non-specific X-linked mental retardation with verbal disability (BDOAS 10, 1-100). MRX23 is tightly linked to the markers DXS1220 (Z = 3.76 at [theta] = 0.1) and DXS424 (Z = 3.9 at [theta] = 0.06). Multipoint linkage analysis, taking five loci (DXS1072-0.07-DXS1220-0.014-MRX23-0.01-DXS424-0.08-DXS1001) at a time, gives a maximum LOD score of 6.7 between these two markers. The next most likely location, between DXS424 and DXS1001 is 120-fold less likely. Haplotype analysis also indicates the most likely location for the disease gene is between DXS1220 and DXS424.
More than 100 X-linked mental retardation (MR) syndromes have been described (reviewed in ref. 1 ). Approximately half of the disease genes have been mapped to specific regions of the X chromosome. Many have been associated with specific diagnostic criteria and are listed as specific entities in McKusick's Mendelian Inheritance in Man (2 ). Some investigators have proposed that certain regions of the X chromosome are enriched for genes responsible for MR (3 ). However, because few of the genes have been mapped to single chromosome bands, this hypothesis remains speculative. In this report we describe the mapping of a gene, MRX23, responsible for a non-specific X-linked MR syndrome in a single large family (family 1, page 53 of ref. 4 ). The disease in this family was first described in 1974 (4 ) and the pedigree updated in 1984 (5 ). We now describe the mapping of the gene responsible for the disease in this family to between DXS1220 and DXS424, at Xq23-q24.
Linkage mapping has been used to localize the gene responsible for a non-specific X-linked MR syndrome. A detailed clinical description of this family has been published elsewhere (4 ,5 ). Affected males have a non-specific X-linked MR. The only distinguishing feature is that affected males have lower verbal IQs than performance IQs. Several of the affected males have performance IQs above 80; however, because of the lower (12.3 points on average) verbal IQs they are considered retarded. Obligate carrier females were considered unaffected; however, IQs were not determined for these individuals. Cytogenetic studies of the affected males in this family failed to detect either gross chromosome rearrangements or microdeletions when analyzed at the 1600 band level. To localize the gene causing this disease a linkage study using probes that detect polymorphisms was undertaken. Because MRX23 is rare, the mutation rate (µ) was assumed to be 0.0001 and the allele frequency 4µ. These estimates are probably high; however, use of rates an order of magnitude lower (or higher) had little effect on our results (data not shown).
DNA samples were obtained from as many potentially informative family members as possible (Fig. 1 ). The same numbering system used previously (5 ) has been retained to allow comparison with the detailed clinical descriptions of various family members. For the initial analyses 23 markers were genotyped on the potentially informative family members. Table 1 presents the two point analyses between the disease gene and the most informative markers tested. Once tentative linkage with DXS1001 was obtained, all available markers in the region also were typed. Two loci, DXS1220 (Z = 3.76 at [theta] = 0.1) and DXS424 (Z = 3.9 at [theta] = 0.06), show the strongest evidence of linkage to MRX23. Weaker evidence for linkage is detected with more distal markers. The order and distance (Kosambi cM) of markers in this region, obtained from the 2D map obtained online from the Washington University server (http://www.genlink.wustl.edu), is: DXS1072-1.3-DXS1105-6.7-DXS1220-2.4-DXS424-7.7-DXS1001-13.4-DXS994. A more recent map, based on STS mapping (6 ) (http://www-genome.wi.mit.edu), inverts markers DXS1072 and DXS1105 relative to the above map. This inversion eliminates several double recombination events from the data set in the family we describe. Therefore, we have combined the data from these two sources and used the following order and distances in the multipoint analyses: DXS1105-1.3-DXS1072-6.7-DXS1220-2.4-DXS424-7.7-DXS1001-13.4-DXS994. LINKMAP analyses using all the markers in Table 1 indicate the most likely location for MRX23 is between DXS1220 and DXS424 with a maximum LOD score of 6.7. The next most likely location, between DXS424 and DXS1001 is 120-fold less likely. For all other intervals the odds were at least 10 000-fold less likely than between DXS1220 and DXS424. The genotypes of selected family members are shown in Figure 1 . Several females (IV-8,10; V-6,12,22) who did not have affected male offspring also were genotyped. To conserve confidentiality the genotypes of these individuals are not shown. However, the inclusion of these individuals frequently allowed the genotypes of key males, and therefore phase in their female offspring, to be inferred. Two recombination events (arrows, Fig. 1 ), in phase known females V-3 and V-16, detected in males VI-5 and VI-25, respectively, also indicate the disease gene is located between DXS1220 and DXS424.
We wish to thank the family members who donated blood, and many physicians who obtained blood samples, thus making the study possible. Financial support was provided by a grant from The Arc, a national organization for the study of mental retardation.
7 Arveiler, B., Alembik, Y. and Hanauer, A. (1988) Linkage analysis suggests at least two loci for X-linked non-specific mental retardation. Am. J. Med. Genet. 30, 473-483. MEDLINE Abstract
8 Yarbrough, K.M. and Howard-Peebles, P.N. (1976) X-linked non specific mental retardation. Report of a large kindred. Clin. Genet. 9, 125-130. MEDLINE Abstract
9 Gedeon, A.K., Keinänen, M., Adès, L.C., Kääriainen, H., Gécz, J., Baker, E., Sutherland, G.R. and Mulley, J.C. (1995) Overlapping submicroscopic deletions in Xq28 in two unrelated boys with developmental disorders: Identification of a gene near FRAXE. Am. J. Hum. Genet. 56, 907-914.MEDLINE Abstract
10 Fasman, K.H., Cuticchia, A.J. and Kingsbury, D.T. (1994) The GDB(TM) Human Genome Data Base anno 1994. Nucleic Acids Res. 22, 3462-3469. MEDLINE Abstract
11 Bell, G.I., Karam, J.H. and Rutter, W.J. (1981) Polymorphic DNA region adjacent to the 5' end of the human insulin gene. Proc. Natl Acad. Sci. USA. 78, 5759-5763. MEDLINE Abstract
12 Sambrook, J., Fritsch, E.E. and Maniatis, T. (1989) Molecular Cloning. A laboratory manual, 2nd edn. Cold Spring Harbor, New York: Cold Spring Harbor Laboratory Press.
13 Reed, K.C. and Mann, D.A. (1985) Rapid transfer of DNA from agarose gels to nylon membranes. Nucleic Acids Res. 13, 7207-7221. MEDLINE Abstract
14 Feinberg, A.P. and Vogelstein, B. (1983) A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal. Biochem. 132, 6-13. MEDLINE Abstract
15 Powers, P.A., Gregg, R.G., Lalley, P., Liao, M. and Hogan, K. (1991) Assignment of the human gene for the [alpha]1-subunit of the cardiac DHP-sensitive Ca2+ channel to chromosome 12p12-pter. Genomics 10, 835-839. MEDLINE Abstract
16 Sakai, R.K., Scharf, S., Faloona, F., Mullis, K.B., Horn, G.T., Erlich, H.A. and Arnheim, N. (1985) Enzymatic amplification of [beta]-globin genomic sequences and restriction site analysis for diagnosis of sickle cell anemia. Science 230, 1350-1354.
17 Lathrop, G.M. and Lalouel, J.M. (1984) Easy calculation of lod scores and genetic risks on small computers. Am. J. Hum. Genet. 36, 460-465. MEDLINE Abstract
18 Freimer, N.B., Sandkuijl, L.A. and Blower, S.M. (1993) Incorrect specification of marker allele frequencies: Effects on linkage analysis. Am. J. Hum. Genet. 52, 1102-1110. MEDLINE Abstract
*To whom correspondence should be addressed at: 707 Waisman Center, 1500 Highland Avenue, Madison, WI 53706, USA
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