Nonspecific X-linked Mental Retardation Research Articles

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

We report on a family in which nonsyndromal 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 theta = 0.0 and marker DXS1108 in Xq28 with a lod score of 3.82 at theta = 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.

Linkage analysis in three families with nonspecific X‐linked mental retardation

Nonspecific X-linked mental retardation (XLMR) is a common disorder. The number of genes involved in this condition is not known, but it is estimated to be more than 10. We present a clinical and linkage study on 3 families with XLMR. All families were analyzed using highly polymorphic markers covering the X chromosome; screening for the fragile X mutation was negative. The first family (MRX 36) consisted of 1 female and 4 male patients in 3 generations and 7 healthy individuals. Considering the female as an expressing heterozygous carrier, a maximum LOD score of 3.41 was reached in region Xp21.2–Xp22.1. Considering her phenotype to be unknown, a LODmax of 1.97 was reached in the same region. The second family consisted of 5 affected and 6 healthy males with mild to borderline mental retardation. Linkage analysis using an X-linked recessive model with full penetrance and no phenocopies excluded linkage over almost the entire X chromosome. Using alternative models, including an affecteds-only analysis, a LODmax of 1.49 was found in region Xq24–28. The third family, consisting of 4 male patients with moderate mental retardation in 1 generation yielded a LODmax of 0.9 in region Xp22.13–11.3. However, even in this small pedigree, exclusion mapping was able to exclude very large parts of the X chromosome and in this way identify a likely candidate region. © 1996 Wiley-Liss, Inc.

Further linkage evidence for localization of mutational sites for nonsyndromic types of X-linked mental retardation at the pericentromeric region.

We used several microsatellite markers scattered along the X chromosome to search for linkage relationships in a large Sardinian pedigree segregating for nonspecific X-linked mental retardation (MRX). Markers DXS573 and AR, located at chromosomal subregions Xp11.4-p11.22 and Xq11.2-q12, respectively, were found to segregate in full concordance with the disease, leading to a LOD score of 4.21 at zero recombination value. Recombination with the disease was found with markers MAOB and DXS454 located at Xp11.4-p11.3 and Xq21.1-q22, respectively; accordingly, markers distal to Xp11.4 and Xq22 also segregated independently of the disease. These findings provide strong linkage evidence in favor of the localization of one MRX mutational site in the pericentromeric region of the human X chromosome, justifying the assignment of a new symbol (MRX26) to our pedigree. Finally, on the basis of the recombinational events observed in the Xq21-q22 region, we have been able to refine the assignment of marker DXS456 to Xq21.33-q22.

Cloning and characterization of DXS6673E, a candidate gene for X-linked mental retardation in Xq13.1.

In several families with non-specific X-linked mental retardation (XLMR) linkage analyses have assigned the underlying gene defect to the pericentromeric region of the X chromosome, but none of these genes have been isolated so far. Here, we report on the cloning and characterization of a novel gene, DXS6673E, that maps to Xq13.1, is subject to X-inactivation and is disrupted in the 5' untranslated region by a balanced X;13 translocation in a mentally retarded female. The DXS6673E gene is highly conserved among vertebrates and its expression is most abundant in brain. It encodes a hydrophilic protein of 1358 amino acids (aa) that does not show sequence homology to other known proteins. A segment of this protein consisting of neutral and hydrophobic aa with a proline residue in every second position may represent a transmembrane domain. Almost complete sequence identity was found between the 3' end of the DXS6673E gene and two expressed sequence tags (ESTs) and between the 5' end of the DXS6673E gene and a third EST. Moreover, weaker sequence similarity was observed between coding regions and two other ESTs.

Identification by STS PCR screening of a microdeletion in Xp21.3-22.1 associated with non-specific mental retardation

X-linked non-specific mental retardation (MRX) is a heterogeneous condition in which mental retardation (MR) appears to be the only consistent manifestation. The genetic and phenotypic heterogeneity exclude any possibility of pooling families and, therefore, of fine-mapping the related disease genes. In order to identify genomic critical regions involved in the MRX condition assigned to Xp21.3-22.1 region, we have implemented the PCR screening of non fragile X MR patients for the presence of deletions in this region. The amplification by PCR of 12 markers located between POLA and DXS704 using genomic DNA from 192 MR males led to the identification, in a 9 year old mentally retarded boy, of a microdeletion which extends from DXS1202 to DXS1065. None of the known genes, POLA, MAGE genes cluster, DAX1, GK and DMD, that map in the Xp21.3-22.1 region is affected by this deletion. This approach, which could easily be applied to several other MRX loci, allowed not only a confirmation of the presence of a potential locus in Xp21.3-22.1 involved in non-specific mental retardation, but also a better definition of the genomic critical region corresponding to this locus.

Localization of a non-specific X-linked mental retardation gene, MRX23, to Xq23-q24.

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-DXS 424-0.08-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.

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 theta = 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.

Pericentromeric genes for non‐specific X‐linked mental retardation (MRX)

Extensive linkage analyses in three families with non-specific X-linked mental retardation (MRX) have localized the gene in each family to the pericentromeric region of the chromosome. The MRX17 gene is localized with a peak lod of 2.41 (theta = 0.0) with the trinucleotide repeat polymorphism at the androgen receptor (AR) gene locus. This gene lies in the interval between the markers DXS255 and DXS990, as defined by recombinants. The MRX18 gene maps to the interval between the markers DXS538 and DXS1126, with a peak lod score of 2.01 (theta = 0.0) at the PFC gene locus. In the third family (Family E) with insufficient informative meioses for assignment of an MRX acronym, the maximum lod score is 1.8 at a recombination fraction of zero for several marker loci between DXS207 and DXS426. Exclusions from the regions of marker loci spanning Xq support the localization of the MRX gene in Family E to the pericentromeric region. Localizations of these and other MRX genes have determined that MRX2 and MRX19 map to distal Xp, MRX3, and MRX6 map to distal Xq, whilst the majority cluster in the pericentromeric region. In addition, we confirm that there are at least two distinct MRX genes near the centromere as delineated by the non-overlapping regional localizations of MRX17 and MRX18. Determination of these non-overlapping localizations is currently the only means of classifying non-syndromal forms of mental retardation and determining the minimum number of MRX loci.

Non-specific X-linked mental retardation: linkage analysis in MRX2 and MRX4 families revisited.

We have previously reported linkage analysis in 3 families with non-specific X-linked mental retardation (XLMR). This used RFLPs and was limited by the relatively low informativeness and density of markers available. We have performed a new linkage analysis using microsatellites (including new Genethon markers) in the two most informative families. In the MRX2 family, a lod score of 2.61 at theta = 0.05 had previously been obtained with DXS85 in Xp22.2. We now report a tighter linkage with AFM 135xe7 (DXS989, z = 4.62 at theta = 0.00) and established the order DXS85-DXS207-DXS999 (AFM234 y12)-MRX2, DXS365, DXS1052 (AFM 163yh2), DXS989-DXS1065 (AFM224zf2), DMD 3'. The localization of MRX2 in Xp22.2-p22.1 is thus clearly different from the more distal MRX gene defined by patients with contiguous gene syndromes. In the MRX4 family, a maximum lod score of 2.53 at theta = 0.00 had been obtained with DXS159 in Xq13. Our present study did not show recombination from ALAS2 in Xp11.21 to DXS441 in Xq13.3 (z = 3.38 at theta = 0.00 for the latter marker) and the closest flanking markers are DXS255 in Xp11.22 and DXYS1 in Xq21.3. Reduced recombination around the centromere prevents precise mapping. The localisation of MRX4 overlaps with that of several other MRX families.

Localization of a Gene Responsible for Nonspecific Mental Retardation (MRX9) to the Pericentromeric Region of the X Chromosome

Nonspecific X-linked mental retardation (MRX) includes several distinct entities with mental retardation but without additional distinguishing features. The MRX family reported here has been classified previously as MRX9. In this study, we performed linkage analysis of MRX9 with a panel of 43 polymorphic DNA markers dispersed over chromosome X. Two-point linkage analysis revealed lod scores of 3.52 and 3.82 at 0% recombination for OATL1 and MAOA, both located in Xp11.2-p11.4. Lod scores for linkage with PGK1P1, DXS106, and DXS132, all located in Xq11-q13, were 3.83, 3.82, and 3.52, respectively, all at 0% recombination. Multipoint linkage analysis showed two peaks with MAOA and DXS132/DXS106, respectively. Analysis of recombinational events indicated a position of the MRX9 gene between DXS164 and DXS453. These findings are compatible with a location of the MRX9 gene in the pericentromeric region of the X chromosome at Xp21-q13.

Linkage to Xq28 in a family with nonspecific X-linked mental retardation.

Linkage analysis was performed in a family with nonspecific X-linked mental retardation (MRX). Affected individuals had no clinical characteristics other than mental retardation. Linkage was detected to the marker loci DXS477, DXS465, DXS52, DXS15 and F8C with maximum lod scores of 1.70, 1.32, 2.52, 1.70, and 1.09, respectively (theta = 0.0). The results strongly indicate that the gene for mental retardation in the family studied maps close to DXS52.

Physical fine mapping of genes underlying X-linked deafness and non fra (X)-X-linked mental retardation at Xq21.

Linkage studies and cytogenetically visible deletions associated with nonspecific X-linked mental retardation (XLMR) and a specific form of deafness (DFN3) have indicated that the genes responsible for these disorders are located at Xq21. Using DNA probes from this region, we have studied several overlapping deletions spanning different parts of Xq21. This has enabled us to assign the DFN3 gene and a gene for nonspecific XLMR to an interval that encompasses the locus DXS232 and that is flanked by DXS26 and DXS121.

Characterization of a highly polymorphic dinucleotide repeat 150 KB proximal to the fragile X site.

Fragile X [fra (X)] syndrome is a frequently encountered form of mental retardation and is inherited as an X-linked semi-dominant trait with reduced penetrance. We report here the characterization of a highly polymorphic dinucleotide repeat, DXS 548, which is approximately 150 kb proximal to the fra(X) site and the associated FMR-1 gene. DXS 548 is tightly linked to the fra (X) syndrome locus (FRAXA) without recombination (LOD = 9.07 with q of 0) in selected families with crossovers between FRAXA and very closely linked flanking markers. This dinucleotide repeat could be useful in determining the parental origin of a new fra (X) mutations and evaluating the role of FMR-1 in X-linked non-specific mental retardation.

XLMR genes: update 1992.

Up to now, we have identified 77 X-linked conditions in which mental retardation is the primary or a major component manifestation. These conditions were subdivided into 2 categories, designated respectively "X-linked mental retardation syndromes" and "Non-specific X-linked mental retardation". Forty genes have been regionally mapped onto the X chromosome. However, in several instances the data were derived from a single family and most lod scores were less than 3.0.

Alguns aspectos genéticos do atraso mental ligado ao cromossoma X.

X-Linked Mental Retardation constitutes an important pathologic entity in genetics. The overall significance, history and background of the concept of X-Linked mental retardation is reviewed with a special mention to the cases referenced under the term non-specific X-Linked mental retardation. The concept of lod-score has brought some improvement in the clinical delineation of the X-Linked mental retardation syndromes with some recent reports of suggestive linkage studies. The fragile-X syndrome is discussed with a special focus on reports of X-linked mental retardation with X chromosomal deletions or duplications. Linkage and molecular studies are reported viewing genetic approaches based on restriction fragment length polymorphisms. DNA probes spanning the length of the X and Y chromosomes which may prove critical to the development of diagnostic tests are referred. Computer assistance for a compilation of clinical findings in the X-linked mental retardation syndromes is specified as a diagnostic review and assistance program to check on the various entities. A joint collaborative investigation is reported to ascertain families with X-linked mental retardation in order to develop direct and linkage studies for the diagnosis of there disorders.

Linkage analysis in a large family with nonspecific X-linked mental retardation.

We report on a large 5-generation family with "nonspecific" X-linked mental retardation. Nine living affected males have an IQ between 50 and 70 but have normal stature, facial appearance, and testicular volumes and no other abnormalities. Two obligate carrier females had borderline intellectual abilities and visual-psychomotor difficulties similar to those seen in affected males. Results of chromosome studies, including fragile X, were normal in males and females. Linkage analysis was undertaken, with 19 X-specific chromosomal restriction fragment length polymorphisms (RFLPs), giving a maximal LOD score of 1.60 at a 0.10 recombination fraction for F9, suggesting a localization to distal Xq for the mutant gene in this family.

Computerized approach to X‐linked mental retardation syndromes

Photographs of normal and abnormal relatives with X-linked mental retardation (XLMR) and clinical data are combined in a Macintosh II computer system to provide an objective and versatile means of evaluating developmental abnormalities. The system includes a flatbed scanner for the entry of photographs and text, additional memory to enhance resolution of photographs, and several programs which facilitate searches for keywords. The primary advantages of the system include an easy interaction between descriptive words and photographs, and rapid comparison of whole faces and specific traits from many individuals. Information within families and between disorders can easily be compared in coded or uncoded fashion. Data from the 34 currently described syndromes emerging from the category of "non-specific XLMR" are being used to develop and test this approach. Neither standard photographs nor most computerized diagnostic systems permit this flexibility. Ultimately, this approach will provide a valuable diagnostic and teaching aid.

Gene for non‐specific X‐linked mental retardation maps in the pericentromeric region

Linkage analysis was carried out in a large four-generation German family segregating for non-specific X-linked mental retardation. Affected males have moderate intellectual handicap. Speech delay, deviant behaviour, and hyperactivity have also been reported. Head circumference and testicular volumes are normal. Cytogenetic analysis failed to show evidence for fragile site or structural abnormality of the X chromosome. None of the obligatory carriers shows any clinical symptoms. Close linkage without recombination (lod scores 1.74 to 2.05) has been found between the disease locus (MRX1) and the polymorphic DNA loci DXS7 (Xp11.4-p11.3), MAOA (Xp11.3-p11.23), DXS255 (Xp11.22), and DXS159 (Xq12) suggesting that the gene responsible for the disease in this family maps in the pericentromeric region of the X chromosome. Linkage data obtained with the flanking marker loci OTC (Xp21.1) and DXS95 (Xq21.2-q21.3) also were compatible with this localization of the MRX1 gene. Close linkage to loci from Xp22, Xq22, Xq24-25, or Xq28 could be excluded.

Contiguous gene syndromes due to deletions in the distal short arm of the human X chromosome.

Mendelian inherited disorders due to deletions of adjacent genes on a chromosome have been described as "contiguous gene syndromes." Short stature, chondrodysplasia punctata, mental retardation, steroid sulfatase deficiency, and Kallmann syndrome have been found as isolated entities or associated in various combinations in 27 patients with interstitial and terminal deletions involving the distal short arm of the X chromosome. The use of cDNA and genomic probes from the Xp22-pter region allowed us to identify 12 different deletion intervals and to confirm, and further refine, the chromosomal assignment of X-linked recessive chondrodysplasia punctata and Kallmann syndrome genes. A putative pseudoautosomal gene affecting height and an X-linked non-specific mental retardation gene have been tentatively assigned to specific intervals. The deletion panel described is a useful tool for mapping new sequences and orienting chromosome walks in the region.

Linkage analysis suggests at least two loci for X‐linked nonspecific mental retardation

Epidemiological studies have suggested that non-specific X-linked mental retardation (XLMR) might be at least as frequent as the fragile X syndrome. The identification of all mutations causing XLMR would thus appear of prime importance. In the absence of other clinical signs the problem of genetic heterogeneity is acute. This can be partly overcome by the analysis of large families. We have been able to perform linkage analysis in 3 such families. The condition in family 1 was described as clinically resembling the fra (X) syndrome by Proops et al [1983]: the kindred includes 7 affected males in 3 sibships. Family 2 from Denmark has affected males in 4 generations; however, several affected relatives in this extended pedigree are deceased. Family 3 from France counts 6 affected males in two sibships. The families were analysed with about 25 X-linked markers. Linkage with markers in Xp22.2-p22.3 was found in family 1: z(theta) = 2.62 at theta = 0.06 for DXS85 (probe 782). Suggestion of linkage was found in family 2 with both the Duchenne muscular dystrophy region (DXS164 in Xp21.2) and with DXS1 (Xq11-q12). In family 3, DXS159 (Xq12-q13) gave a lod score of 2.53 at theta = 0; results were compatible with localisation of the putative XLMR locus in this family proximal to DXYS1 (Xq21). These data suggest that at least two non-specific XLMR loci could exist, one in Xp22 and the other in the q12-q13 region.