A gene for nonsyndromic X-linked mental retardation (MRX77) maps to Xq12-Xq21.33

Nonsyndromic X-linked mental retardation (MRX) is a highly heterogeneous condition in which mental retardation appears to be the only consistent manifestation. According to the most recent data, 77 MRX families with a lod score of >2 have been mapped and eight genes have been cloned. We hereby report on a linkage analysis performed on a Greek family with apparently nonsyndromic MRX. The affected males have moderate to severe mental retardation, severe speech problems, and aggressive behavior. Two-point linkage analysis with 26 polymorphic markers spanning the entire X chromosome was carried out. We could assign the causative gene to a 27 Mb interval in Xq12-Xq21.33. The maximum LOD score was found for markers DXS1225, DXS8114, and DXS990 at 2.36, 2.06, 2.06, respectively at theta = 0.00. Recombination was observed for DXS983 at the proximal side and DXS6799 at the distal side. Nineteen other MRX families have been described with a partial overlapping disease gene interval in proximal Xq. No mutations were found in the MRX77 family for three known or candidate MRX genes, from this region OPHN1, RSK4, and ATR-X. These data indicate that the Xq12-Xq21.33 interval contains at least one additional MRX gene.     

Regional localization of a nonspecific X-linked mental retardation gene (MRX59) to Xp21.2-p22.2.

Linkage analysis was performed on a four-generation family with nonspecific mental retardation (MRX59). The five affected males, ranging in age from 2 years to 52 years, have a normal facial appearance and mild to severe mental impairment. Four obligate carriers are physically normal and not retarded. A maximum LOD score of 2.41 at straight theta = 0.00 was observed with the microsatellite markers, DMD45 in Xp21.2, DXS989 in Xp22.1, and DXS207 in Xp22.2. Recombinations were detected within the dystrophin gene (DMD) in one of the affected males and between DXS207 and DXS987 in Xp22.2 in one of the carriers. These recombinants define the proximal and distal boundaries of a candidate gene region. Genetic localization of this familial condition made prenatal diagnosis informative for one of the obligate carriers.     

Refined 2.7 centimorgan locus in Xp21.3-22.1 for a nonspecific X-linked mental retardation gene (MRX54).

Nonspecific X-linked mental retardation (MRX) is a heterogeneous condition in which mental retardation (MR) appears to be the only consistent manifestation. A large genetic interval of assignment obtained on individual families by linkage analysis, genetic, heterogeneity, and phenotypic variability usually are major obstacles to fine-map and identify the related disease genes. Here we report on a large Tunisian family (MRX54) with an MRX condition. X-linked recessive inheritance is strongly suggested by the segregation of MR through seven unaffected carrier females to 14 affected males in two generations. Two-point linkage analysis demonstrated significant linkage between the disorder and several markers in Xp21.3-22.1 (maximum LOD score Zmax = 3.56, recombination fraction 0 = 0 at DXS1202), which was confirmed by multipoint linkage analyses. Recombinant events observed with the flanking markers DXS989 and DXS1218 delineate a refined locus of approximately 2.7 cM in accordance with the physical distance between these two markers. The small interval of assignment observed in this family overlaps not only with nine large MRX loci previously reported in Xp21.3-22.1 but also with two inherited microdeletions in Xp21.3-22.1 involved in nonspecific MR. Although the involvement of several genes located in the Xp21.3-22.1 region cannot be ruled out, data reported in this study could be used as a starting point for the search of such gene(s).     

Mapping of a gene for nonspecific X-linked mental retardation (MRX 75) to Xq24-q26

Nonspecific X-linked mental retardation is a heterogeneous condition consisting of nonsyndromal mental retardation in males. It is caused by mutation in one of several genes on the X chromosome (MRX genes). Here we report on the localization of a presumptive MRX gene to chromosomal region Xq24-q26 in a German family with nonspecific X-linked mental retardation (MRX 75, HUGO Human Gene Nomenclature Committee). Two point linkage analysis with 23 informative markers gave a lod score of 2.53 at theta = 0 for markers DXS425, DXS1254, DXS1114, and HPRT.     

Localization of a gene for X-linked nonspecific mental retardation (MRX24) in Xp22.2–p22.3

Nonspecific X-linked mental retardation (MRX) includes several distinct genetic entities in which mental retardation is not associated with additional distinguishing physical changes. We report linkage data in a Spanish family with MRX, using polymorphic DNA markers distributed over the X chromosome. Two-point linkage analysis demonstrated close linkage between the MRX locus and DXS85 in Xp22.3 with a peak lod score of 2.28 at a Ø = 0.00. Analysis of multiple informative meioses suggested a localization of the MRX locus (MRX24) between DXS278 and DXS207. Multipoint linkage analysis resulted in a maximum LOD score of 2.45 at 3 cM proximal to DXS85, and allowed us to reject a localization of the MRX24 gene in all other regions from Xp21–Xqter. These findings localize the MRX24 gene in the chromosomal region Xp22.2–p22.3. © 1995 Wiley-Liss, Inc.     

Localization of non-specific X-linked mental retardation gene (MRX73) to Xp22.2

Clinical and molecular studies are reported on a family (MRX73) of five males with non-specific X-linked mental retardation (XLMR). A total of 33 microsatellite and RFLP markers was typed. The gene for this XLMR condition was been linked to DXS1195, with a lod score of 2.36 at theta = 0. The haplotype and multipoint linkage analyses suggest localization of the MRX73 locus to an interval of 2 cM defined by markers DXS8019 and DXS365, in Xp22.2. This interval contains the gene of Coffin-Lowry syndrome (RSK2), where a missense mutation has been associated with a form of non-specific mental retardation. Therefore, a search for RSK2 mutations was performed in the MRX73 family, but no causal mutation was found. We hypothesize that another unidentified XLMR gene is located near RSK2.     

Localization of two X-linked mental retardation (XLMR) genes to Xp: MRX37 gene at Xp22.31-p22.32 and a putative MRX gene on Xp22.11-p22.2

MRX genes of 2 families with X-linked mental retardation (XLMR) were localized by linkage analysis. In family A, the gene was mapped to Xp22.31–p22.32, with significant LOD scores to various Xp22 markers within a distance of 6 Mb between DXS1223 and DXS1224. The MRX gene of this family was designated MRX37. In a mentally retarded female who is a carrier of the MRX37 gene, a random pattern of X inactivation was demonstrated. In family B, a positive LOD score, although not significant (< + 2), was found with the marker DXS1202 at Xp22.11–p22.2. © 1996 Wiley-Liss, Inc.     

Nonsyndromic X-linked mental retardation: review and mapping of MRX29 to Xp21

The gene responsible for nonsyndromic mental retardation in a family with 7 affected males has been localized to Xp21. The maximal two-point lod score was 3.31 for tight linkage to marker DXS1202 in Xp21.3-p22.3 with crossovers between the 3' portion of the DMD gene (DXS 1234) proximally and locus DXS989 distally. The XLMR gene in this family has been assigned the designation MRX29. The localization overlaps with at least six other MRX entities linked to the distal short arm of the X chromosome.     

Nonsyndromic X-linked mental retardation: Mapping of MRX58 to the pericentromeric region

An Austrian family with nonsyndromic X-linked mental retardation (MRX) is reported in which the obligatory carrier females are normal, and 5 affected males have mild to moderate mental retardation. Linkage analysis indicated an X pericentromeric localization, with flanking markers DXS989 and DXS1111 and a maximum multipoint LOD score of 2.09 (θ = 0) for the 7 cosegregating markers DXS1243, CybB, MAOB, DXS988, ALAS2, DXS991, and AR. MRX58 thus mapped within a 50-cM interval between Xp11.3 and Xq13.1 and overlapped with 23 other MRX families already described. This pericentromeric clustering of MRX families suggests allelism, with a minimum of 2 X-linked mental retardation (XLMR) genes in this region. Am. J. Med. Genet. 86:102–106, 1999. © 1999 Wiley-Liss, Inc.     

A gene for nonspecific X-linked mental retardation (MRX41) is located in the distal segment of Xq28

We report on a family in which non-syndromal mild to moderate mental retardation segregates as an X-linked trait (MRX41). Two point linkage analysis demonstrated linkage between the disorder and marker DXS3 in Xq21.33 with a lod score of 2.56 at θ = 0.0 and marker DXS1108 in Xq28 with a lod score of 3.82 at θ = 0.0. Multipoint linkage analysis showed that the odds for a location of the gene in Xq28 vs Xq21.33 are 100:1. This is the fourth family with non-specific X-linked mental retardation with Xq28-qter as the most likely gene localization. © 1996 Wiley-Liss, Inc.     

Linkage mapping of a nonspecific form of X-linked mental retardation (MRX53) in a large Pakistani family

Nonspecific X-linked mental retardation is a nonprogressive, genetically heterogeneous condition that affects cognitive function in the absence of other distinctive clinical manifestations. We report here linkage data on a large Pakistani family affected by a form of X-linked nonspecific mental retardation. X chromosome genotyping of family members and linkage analysis allowed the identification of a new disease locus, MRX53. The defined critical region spans approximately 15 cM between DXS1210 and DXS1047 in Xq22.2-26. A LOD score value of 3.34 at no recombination was obtained with markers DXS1072 and DXS8081.     

Mapping to distal Xq28 of nonspecific X-linked mental retardation MRX72: linkage analysis and clinical findings in a three-generation Sardinian family

Families with mentally retarded males found to be negative for FRAXA and FRAXE mutations are useful in understanding the genetic basis of X-linked mental retardation. According to the most recent data (updated to 1999), 69 MRX loci have been mapped and 6 genes cloned. Here we report on a linkage study performed on 20 subjects from a 4-generation Sardinian family segregating a non-specific X-linked recessive mental retardation (XLMR)(MRX72) associated with global delay of all psychomotor development. Five of 8 affected males have been tested for mental age, verbal and performance skills and behavioral anomalies; mental impairment ranged from mild to severe. Only minor anomalies were present in the affected subjects. Two-point linkage analysis based on 28 informative microsatellites spanning the whole X chromosome demonstrated linkage between the disorder and markers DXS1073 and F8c in Xq28 (maximum Lod score of 2. 71 at straight theta = 0.00). Multipoint linkage analysis confirmed the linkage with a Z(max) of 3.0 at straight theta = 0.00 at DXS1073 and F8c. Recombination in an affected male at DXS1073 and F8c allowed us to delimit centromerically and telomerically the region containing the putative candidate gene. The region, where MRX72 maps, overlaps that of another MRX families previously mapped to Xq28, two of which harbored mutations in GDI. Involvement of this gene was excluded in our family, suggesting another MRX might reside in Xq28.     

Regional localization of two genes for nonspecific X-linked mental retardation to Xp22.3–p22.2 (MRX49) and Xp11.3–p11.21 (MRX50)

Two families with nonspecific X-linked mental retardation (XLMR) are presented. In the first family, MRX49, 5 male patients in 2 generations showed mild to moderate mental retardation. Two-point linkage analysis with 28 polymorphic markers, dispersed over the X-chromosome, yielded a maximal LOD score of 2.107 with markers DXS7107 and DXS8051 at θ = 0.0, localizing the MRX49 gene at Xp22.3-p22.2, between Xpter and marker DXS8022. Multipoint linkage analysis showed negative LOD values over all other regions of the chromosome. In the second family, MRX50, 4 males in 2 generations showed moderate mental retardation. Pairwise linkage analysis with 28 polymorphic markers yielded a LOD score of 2.056 with markers DXS8054, DXS1055, and DXS1204, all at θ = 0.0. Flanking markers were DXS8012 and DXS991, situating the MRX50 gene at Xp11.3-Xp11.21, in the pericentromeric part of the short arm of the X chromosome. Am. J. Med. Genet. 73:474–479, 1997. © 1997 Wiley-Liss, Inc.     

New X-linked mental retardation syndrome with the gene mapped tentatively in Xp22.3

X-linked mental retardation (XLMR) is genetically heterogeneous and clinically variable. We describe a new XLMR syndrome of severe mental retardation and multiple congenital anomalies. Two sisters have (with 3 different partners) 3 severely handicapped sons. In 2 cases, oligohydramnios and intrauterine growth retardation were noted. Common anomalies included a square-shaped face, high and broad forehead, frontal bossing, downward slant of palpebral fissures, hypertelorism, epicanthic folds, long philtrum, thin upper lip, and apparently low-set ears. One boy has bilateral microphthalmos and sclerocornea, and his cousin has atrophy of the optic nerve. All 3 patients are blind and have profound statomotor and mental retardation, seizures, and a grossly abnormal electroencephalographic pattern. Additional findings are short stature, delayed bone maturation, hydronephrosis, vesicorenal reflux, cryptorchidism, clinodactyly of the 5th fingers, and transverse palmar creases. The karyotype is normal (46,XY). Segregation analysis showed perfect coinheritance between the clinical phenotype and alleles at several loci in Xp22.3, whereas recombinants were identified with marker loci from Xp22.2-qter. Analysis of multiple informative meioses suggests that the disease locus maps in Xp22.3 distal to DXS16. © 1996 Wiley-Liss, Inc.     

Gene for nonspecific X-linked mental retardation (MRX 47) is located in Xq22.3-q24

We describe a large family with nonspecific X-linked mental retardation (MRX 47). An X-linked recessive transmission is suggested by the inheritance from the mothers in two generations of a moderate to severe form of mental retardation in six males, without any specific clinical findings. Two point linkage analysis demonstrated significant linkage between the disorder and two markers in Xq23 (Zmax = 3.75, θ = 0). Multipoint linkage analyses confirmed the significant linkage with a maximum lod score (Z = 3.96, θ = 0) at DXS1059. Recombination events observed with the flanking markers DXS1105 and DXS8067 delineate a 17cM interval. This interval overlaps with several loci of XLMR disorders previously localized in Xq23–q24, which are reviewed herein. Am. J. Med. Genet. 72:324–328, 1997. © 1997 Wiley-Liss, Inc.     

A locus for nonspecific X-linked mental retardation mapped to a 22.3 cM region of Xp11.3-q22.3

By using several microsatellite markers scattered along the X chromosome, we studied a Chinese family with nonspecific X-linked mental retardation (MRX84) to search for a region including the MRX84 locus that was linked to the markers. Two-point linkage analysis demonstrated linkage between the disorder and several markers located at Xq22.2, with maximum LOD score Z(max) = 2.41 at recombination fraction theta = 0 for DXS1191 and DXS1230, respectively. Recombination events were observed with flanking markers DXS8080 and DXS456, located at Xp11.3 and Xq22.3, respectively, and a region of approximately 22.3 cM was defined. Accordingly, markers distal to Xp11.3 and Xq22.3 segregated independently of the disease. The localized region observed in this Chinese family overlaps with 29 other MRX loci previously reported in Xp11.3-q22.3. These results should contribute to the identification of the disease gene for the MRX84 disorder.