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. © 2001 Wiley‐Liss, Inc.     

Deletion mapping and X inactivation analysis of a non-specific mental retardation gene at Xp21.3-Xp22.11

We report on deletion mapping and X inactivation analysis of a gene for X linked non-specific mental retardation (MRX) at Xp21.3-Xp22.11, on the basis of molecular studies in two families with Xp microdeletions involving the DAX-1 gene. In family A, mental retardation (MR) was profound in the older brother with an episode of adrenal crisis, severe in the younger brother with no episode of adrenal crisis, and mild to moderate in the sister and the mother with no signs of adrenal hypoplasia. In family B, MR was absent in the male patient with adrenal hypoplasia. Polymerase chain reaction for 16 loci in the middle of Xp showed that the brothers of family A had a small Xp deletion between DXS7182 and DXS1022, and that the patient of family B had a tiny Xp deletion between DXS319 and DXS1022. Microsatellite analysis for tetranucleotide repeats in the promoter region of the DAX-1 gene and Southern blotting for DAX-1 and DXS28 showed that the sister and the mother of family A were heterozygous for the interstitial deletion. X inactivation analysis for the methylation status of the AR gene and the HPRT gene indicated that the normal X and the deleted X chromosome underwent random X inactivation in both the sister and the mother. The results imply that an MRX gene subject to X inactivation is present in a roughly 4 Mb region between DXS7182 and DAX-1, and that reduced expression of the normal MRX gene caused by random X inactivation results in MR in carrier females.     

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.     

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.     

Regional localization of two non-specific X-linked mental retardation genes (MRX30 and MRX31)

Two genes responsible for X-linked mental retardation have been localised by linkage analysis. MRX30 maps to a 28 cM region flanked by the loci DXS990 (Xq21.3) and DXS424 (Xq24). A significant multipoint lod score of 2.78 was detected between the loci DXS1120 and DXS456. MRX31 maps to a 12 cM region that spans the centromere from DXS1126 (Xp11.23) to DXS1124 (Xq13.3). Significant two-point lod scores, at a recombination fraction of zero, were obtained with the loci DXS991 (Zmax = 2.06), AR (Zmax = 3.44), PGK1P1 (Zmax = 2.06) and DXS453 (Zmax = 3.31). The MRX30 localisation overlaps that of MRX8, 13, 20 and 26 and defines the position of a new MRX gene on the basis of a set of non-overlapping regional localisations. The MRX31 localisation overlaps the localisations of many of the pericentromeric MRX loci (MRX, 1, 4, 5, 7, 8, 9, 12, 13, 14, 15, 17, 20, 22 and 26). There are now at least 8 distinct loci associated with non-specific mental retardation on the X chromosome defined, in order from pter to qter, by localisation for MRX24, MRX2, MRX10, MRX1, MRX30, MRX27, FRAXE and MRX3. © 1996 Wiley-Liss, Inc.     

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.     

X-linked mental retardation with neonatal hypotonia in a French family (MRX15): Gene assignment to Xp11.22-Xp21.1

Linkage analysis was performed in a family with non-specific X-linked mental retardation (MRX 15). Hypotonia in infancy was the most remarkable physical manifestation. The severity of mental deficiency was variable among the patients, but all of them had poor or absent speech. Significant lod scores at a recombination fraction of zero were detected with the marker loci DXS1126, DXS255, and DXS573 (Zmax = 2.01) and recombination was observed with the two flanking loci DXS164 (Xp21.1) and DXS988 (Xp11.22), identifying a 17 cM interval. This result suggests a new gene localization in the proximal Xp region. In numerous families with non-specific X-linked mental retardation (MRX), the corresponding gene has been localized to the paracentromeric region in which a low recombination rate impairs the precision of mapping. © 1996 Wiley-Liss, Inc.     

Regional localization of two MRX genes to Xq28 (MRX28) and to Xp11.4-Xp22.12 (MRX33)

Two genes responsible for a nonspecific form of X-linked mental retardation (MRX28 and MRX33) were localized by linkage analysis with 40 highly polymorphic DNA markers situated along the entire the X chromosome. In family 1, the gene could be mapped within a 14-cM interval at Xq28, distal to the recombining marker DXS1113 (MRX28). The maximum LOD score was 2.75, with DXS52 at ϕ = .0. In family 2, the gene was localized within a 30-cM interval at Xp11.4-22.12 between the recombining markers DXS365 and MAOB, including the DMD gene (MRX33). Maximum LOD scores of 2.82 were obtained with markers DMD-STR49, DMD-DysII, CYBB, and DXS1068. © 1996 Wiley-Liss, Inc.     

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 non‐syndromal 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 Θ = 0 for markers DXS425, DXS1254, DXS1114, and HPRT. Am. J. Med. Genet. 93:290–293, 2000. © 2000 Wiley‐Liss, Inc.     

X-linked mental retardation exhibiting linkage to DXS255 and PGKP1: a new MRX family (MRX14) with localization in the pericentromeric region

Gene localization was determined by linkage analysis in a large French family with X-linked mental retardation (MRX). Seven living affected males were clinically studied and the clinical picture was characterized by moderate to severe mental handicap with poor secondary speech acquisition. Seizures, slight microcephaly, simian crease, anteverted pinnae, and macroorchidism were observed in some patients only. Linkage analysis revealed no recombination between the MRX gene and two loci: DXS255 at Xp11.22 (Zmax = 3.31 at θ= 0.00) and PGKP1 at Xq11.2-q12 (Zmax = 3.08 at 9 = 0.00). One recombination was observed between the gene and the two loci DXS164 at Xp21.2 and DXS441 at Xq13.3, respectively. These results suggested gene localization in the pericentromeric region of the X chromosome, and the LOD scores justified assignment of the symbol MRX14 to this family.     

Fragile (X) X-linked mental retardation I: Relationship between age and intelligence and the frequency of expression of fragil (X)(q28)

Members of eight Saskatchewan families with fragile (X) X-linked mental retardation were studied in an attempt to relate frequency to age and intelligence. The mean IQ of 37 affected men was 35 (range 10–66). The mean IQ of 32 carriers was 88 (range 57–119), and the mean IQ of 13 females who remain at risk for being carriers, have no affected sons, and who failed to demonstrate the fra(X) was 100 (range 78–126). We demonstrated a significant inverse relationship between age and frequency of the fra(X) in carriers and in affected males. However, we demonstrated a more highly significant inverse relationship between frequency of the fra(X) and IQ in carriers but to a lesser extent in affected males. Of 32 carriers, only 3 (9.4%) did not demonstrate the fra(X) after addition of 5-fluoro-2′-deoxyuridine (FUdR) to the folic acid and thymidine-reduced culture medium. From these data we would recommend that chromosome studies in individuals at risk for fra(X) X-linked mental retardation be carried out at the youngest age and that the addition of FUdR to culture medium is useful in carrier identification. It is clear that, in at least the carriers, a lower expression of the fra(X) is highly significantly correlated to higher intelligence.     

A clinical, cytogenetic and familial study of 307 mentally retarded, institutionalized, adult male patients with special interest for fra(X) negative X-linked mental retardation

In this study we report the results of a systematic etiological, clinical genetic study in 307 institutionalized mentally retarded adult males. Special attention is paid to the nosology of X-linked mental retardation. During the survey 63 males with one or more 'Martin Bell'-like features were identified in whom repetitive fragile Xq27-3 screenings were negative. In 13 of them, belonging to 9 different families, pedigree data were compatible with X-linked inheritance. This finding confirms the existence of one (or more) forms of fra(x) negative mental retardation with 'Martin Bell'-like features.     

Blepharophimosis sequence (BPES) and microcephaly in a girl with del(3) (q22.2q23): A putative gene responsible for microcephaly close to the BPES gene?

We report on a girl with the blepharophimosis sequence (BPES), microcephaly of postnatal onset, mild developmental retardation, and a deletion: 46,XX,del(3) (q22.2q23) de novo. A gene for BPES is suspected to be located at 3q23. Almost all cases with interstitial deletions containing 3q23 have not only BPES but also microcephaly and developmental retardation, while those without deletions, including those with apparently balanced translocations, only have BPES. Thus, a putative gene responsible for microcephaly may exist close to BPES gene. BPES, microcephaly, developmental retardation, and primary amenorrhea might constitute a contiguous gene syndrome. © 1993 Wiley-Liss, Inc.     

Studies on the structure and function of the apolipoprotein(a) gene

Lp(a) is an LDL-like lipoprotein that is a major inherited risk factor for atherosclerosis. It is distinguished from Lp(a) by the addition of apolipoprotein(a). The gene structure of apolipoprotein(a) is homologous to plasminogen, and competition with plasminogen activity may account for some of the pathophysiology associated with Lp(a). Six highly related genes have now been identified, and at least four are found in close proximity in overlapping genomic clones. Studies have begun on the regulation of apolipoprotein (a) gene expression, and the human apolipoprotein(a) gene has been inserted into transgenic mice, where it leads to the development of arterial lesions.     

Ongoing hypermutation in the Ig V(D)J gene segments and c-myc proto-oncogene of an AIDS lymphoma segregates with neoplastic B cells at different sites: implications for clonal evolution

To investigate the role of somatic Ig hypermutation in the evolution of AIDS-associated B cell lymphomas, we analyzed the Ig V(D)J and c-myc genes expressed by neoplastic B cells in two extranodal sites, testis and orbit, and clonally related cells in the bone marrow. Testis and orbit B cells expressed differentially mutated but collinear V_HDJ_H, VκJκ and c-myc gene sequences. Shared mutations accounted for 10.2%, 8.4%, and 4.3% of the overall V_HDJ_H, VκJκ, and c-myc gene sequences. Tumor-site specific V_HDJ_H, VκJκ, and c-myc mutations were comparable in frequency, and a single point-mutation gave rise to an EcoRI site in the testis c-myc DNA. Both shared and tumor site-specific V_HDJ_H, VκJκ, and c-myc mutations displayed predominance of transitions over transversions. The “neoplastic” V_HDJ_H sequence was expressed by about 10⁻⁵ cells in the bone marrow, and contained two of the three orbital, but none of the testicular V_HDJ_H mutations. The nature and distribution of the Ig V(D)J mutations found in the κ chain suggested a selection by antigen in testis and orbit. Our data suggest that, in AIDS-associated B cell lymphomas, the Ig hypermutation machinery targets V_HDJ_H, VκJκ, and c-myc genes with comparable efficiency and modalities.     

Ongoing hypermutation in the Ig V(D)J gene segments and c-myc proto-oncogene of an AIDS lymphoma segregates with neoplastic B cells at different sites: implications for clonal evolution

To investigate the role of somatic Ig hypermutation in the evolution of AIDS-associated B cell lymphomas, we analyzed the Ig V(D)J and c-myc genes expressed by neoplastic B cells in two extranodal sites, testis and orbit, and clonally related cells in the bone marrow. Testis and orbit B cells expressed differentially mutated but collinear V_HDJ_H, VκJκ and c-myc gene sequences. Shared mutations accounted for 10.2%, 8.4%, and 4.3% of the overall V_HDJ_H, VκJκ, and c-myc gene sequences. Tumor-site specific V_HDJ_H, VκJκ, and c-myc mutations were comparable in frequency, and a single point-mutation gave rise to an EcoRI site in the testis c-myc DNA. Both shared and tumor site-specific V_HDJ_H, VκJκ, and c-myc mutations displayed predominance of transitions over transversions. The “neoplastic” V_HDJ_H sequence was expressed by about 10⁻⁵ cells in the bone marrow, and contained two of the three orbital, but none of the testicular V_HDJ_H mutations. The nature and distribution of the Ig V(D)J mutations found in the κ chain suggested a selection by antigen in testis and orbit. Our data suggest that, in AIDS-associated B cell lymphomas, the Ig hypermutation machinery targets V_HDJ_H, VκJκ, and c-myc genes with comparable efficiency and modalities.     

Duplication of (2)(q11.1‐q13.2) in a boy with mental retardation and cleft lip and palate: Another clefting gene locus on proximal 2q?

A 4‐year‐old boy with left cleft lip and cleft palate, multiple minor anomalies and developmental delay revealed an abnormal chromosome 2 with enlarged proximal long arm, de novo, in his karyotype. Fluorescence in situ hybridization with a chromosome 2 library and band‐specific YACs confined the duplicated segment to 2q11.1‐q13.2 and indicated a direct tandem duplication due to unbalanced crossover between chromatids. © 2002 Wiley‐Liss, Inc.