The 239AB gene on chromosome 22: a novel member of an ancient gene family

A novel family of genes expressed in human brain has recently been identified. Gene 239FB, transcribed extensively in fetal brain, was isolated from the chromosome 11p13 region associated with mental retardation component of the WAGR (Wilms tumor, aniridia, genitourinary anomalies, mental retardation) syndrome. This report presents a cDNA sequence and expression profile of a related gene, 239AB, isolated from adult brain library, that was mapped to chromosome 22. While similar in structure, the two genes differ in their expression pattern and may have different roles in central nervous system development and function. In contrast to the 239FB, which is expressed predominantly in fetal brain, the 239AB gene is transcribed in adult tissues. Both human genes encode novel proteins of unknown function that are highly conserved from Caenorhabditis elegans to birds and mammals. Phylogenetic analysis suggested that the two lineages of the ancient gene family represented by 239FB and 239AB have been in existence prior to the emergence of modern animals.     

Protein-truncating mutations in ASPM cause variable reduction in brain size

Mutations in the ASPM gene at the MCPH5 locus are expected to be the most common cause of human autosomal recessive primary microcephaly (MCPH), a condition in which there is a failure of normal fetal brain development, resulting in congenital microcephaly and mental retardation. We have performed the first comprehensive mutation screen of the 10.4-kb ASPM gene, identifying all 19 mutations in a cohort of 23 consanguineous families. Mutations occurred throughout the ASPM gene and were all predicted to be protein truncating. Phenotypic variation in the 51 affected individuals occurred in the degree of microcephaly (5-11 SDs below normal) and of mental retardation (mild to severe) but appeared independent of mutation position.     

Loss of allelic heterozygosity at a second locus on chromosome 11 in sporadic Wilms'' tumor cells.

Children with associated Wilms' tumor, aniridia, genitourinary malformations, and mental retardation (WAGR syndrome) frequently have a cytogenetically visible germ line deletion of chromosomal band 11p13. In accordance with the Knudson hypothesis of two-hit carcinogenesis, the absence of this chromosomal band suggests that loss of both alleles of a gene at 11p13 causes Wilms' tumor. Consistent with this model, chromosomes from sporadically occurring Wilms' tumor cells frequently show loss of allelic heterozygosity at polymorphic 11p15 loci, and therefore it has been assumed that allelic loss extends proximally to include 11p13. We report here that in samples from five sporadic Wilms' tumors, allelic loss occurred distal to the WAGR locus on 11p13. In cells from one tumor, mitotic recombination occurred distal to the gamma-globin gene on 11p15.5. Thus, allelic loss in sporadic Wilms' tumor cells may involve a second locus on 11p.     

Further localization of X-linked hydrocephalus in the chromosomal region Xq28

X-linked hydrocephalus (HSAS) is the most frequent genetic form of hydrocephalus. Clinical symptoms of HSAS include hydrocephalus, mental retardation, clasped thumbs, and spastic paraparesis. Recently we have assigned the HSAS gene to Xq28 by linkage analysis. In the present study we used a panel of 18 Xq27-q28 marker loci to further localize the HSAS gene in 13 HSAS families of different ethnic origins. Among the Xq27-q28 marker loci used, DXS52, DXS15, and F8C gave the highest combined lod scores, of 14.64, 6.53 and 6.33, respectively, at recombination fractions of .04, 0, and .05, respectively. Multipoint linkage analysis localizes the HSAS gene in the telomeric part of the Xq28 region, with a maximal lod score of 20.91 at 0.5 cM distal to DXS52. Several recombinations between the HSAS gene and the Xq28 markers DXS455, DXS304, DXS305, and DXS52 confirm that the HSAS locus is distal to DXS52. One crossover between HSAS and F8C suggests that HSAS gene to be proximal to F8C. Therefore, data from multipoint linkage analysis and the localization of key crossovers indicate that the HSAS gene is most likely located between DXS52 and F8C. This high-resolution genetic mapping places the HSAS locus within a region of less than 2 Mb in length, which is now amenable to positional cloning.     

Dedicator of cytokinesis 8 is disrupted in two patients with mental retardation and developmental disabilities

We have identified disruptions in the dedicator of cytokinesis 8 gene, DOCK8, in two unrelated patients with mental retardation (MR). In one patient, a male with MR and no speech, we mapped a genomic deletion of approximately 230 kb in subtelomeric 9p. In the second patient, a female with mental retardation and ectodermal dysplasia and a balanced translocation, t(X;9) (q13.1;p24), we mapped the 9p24 breakpoint to a region overlapping with the centromeric end of the 230-kb subtelomeric deletion. We characterized the DOCK8 gene from the critical 9p deletion region and determined that the longest isoform of the DOCK8 gene is truncated in both patients. Furthermore, the DOCK8 gene is expressed in several human tissues, including adult and fetal brain. Recently, a role for DOCK8 in processes that affect the organization of filamentous actin has been suggested. Several genes influencing the actin cytoskeleton have been implicated in human cognitive function and thus a possibility exists that the rare mutations in the DOCK8 gene may contribute to some cases of autosomal dominant mental retardation.     

The Juberg-Marsidi syndrome maps to the proximal long arm of the X chromosome (Xq12-q21).

Juberg-Marsidi syndrome (McKusick 309590) is a rare X-linked recessive condition characterized by severe mental retardation, growth failure, sensorineural deafness, and microgenitalism. Here we report on the genetic mapping of the Juberg-Marsidi gene to the proximal long arm of the X chromosome (Xq12-q21) by linkage to probe pRX214H1 at the DXS441 locus (Z = 3.24 at theta = .00). Multipoint linkage analysis placed the Juberg-Marsidi gene within the interval defined by the DXS159 and the DXYS1X loci in the Xq12-q21 region. These data provide evidence for the genetic distinction between Juberg-Marsidi syndrome and several other X-linked mental retardation syndromes that have hypogonadism and hypogenitalism and that previously. Finally, the mapping of the Juberg-Marsidi gene is of potential interest for reliable genetic counseling of at-risk women.     

A novel C-T transition within the distal CCAAT motif of the G gamma-globin gene in the Japanese HPFH: implication of factor binding in elevated fetal globin expression.

Hereditary persistence of fetal hemoglobin (HPFH) is a condition characterized by the continued expression of the fetal globin gene in adulthood. Both deletional and nondeletional forms have been described. We studied one Japanese family with two different nondeletional forms of HPFH. Analysis of polymorphic restriction sites in the beta-globin gene cluster suggested that one affecting both G gamma and A gamma globin expression in two members of the family could be associated with unknown conditions not linked to the beta-globin gene loci. Characterization by the polymerase chain reaction (PCR) of another form producing a G gamma-HPFH phenotype in two other members demonstrated a novel C-T transition at the nucleotide -114 within the distal CCAAT motif of the G gamma-globin gene. Using gel retardation assays on various nuclear extracts, we also demonstrated that this novel mutation abolishes the binding of the ubiquitous CCAAT binding factor, CP1 to the distal CCAAT motif of the gamma-globin gene but does not affect the binding of any erythroid specific factor, thereby suggesting a possible role for CP1 in the developmental regulation of fetal globin expression.     

Ataxic gait and mental retardation with absence of the paternal chromosome 8 and an idic(8)(p23.3): imprinting effect or nullisomy for distal 8p genes?

A female child with mild dysmorphisms, motor and mental retardation had a 45,XX,-8,-8,+psu dic(8)(p23.3) karyotype in blood lymphocytes, skin fibroblasts and in a lymphoblastoid cell line. DNA analysis showed that the proposita was nullisomic for the 8pter region distal to D8S264, at less than 1 cM from the telomere. Analysis of DNA polymorphisms of 38 loci spread along the entire chromosome 8 revealed that only maternal alleles were present, distributed in four heterozygous and four homozygous regions. This finding indicated that the rearrangement occurred during maternal meiosis in a chromosome recombinant with a minimum of seven crossovers. To our knowledge this is the first case of uniparental maternal disomy for chromosome 8 and of nullisomy for the distal 1-cM portion of the short arm. The available data are in favour of the assumption that no imprinted genes are present on chromosome 8. Thus, dysmorphisms, motor and mental retardation of the proposita are likely to be caused by the nullisomy for the region distal to D8S264, a region in which a recessive gene for epilepsy with progressive mental retardation is known to be located. Received: 16 December 1996 / Revised: 24 January 1997     

Disruption of the serine/threonine kinase 9 gene causes severe X-linked infantile spasms and mental retardation

X-linked West syndrome, also called "X-linked infantile spasms" (ISSX), is characterized by early-onset generalized seizures, hypsarrhythmia, and mental retardation. Recently, we have shown that the majority of the X-linked families with infantile spasms carry mutations in the aristaless-related homeobox gene (ARX), which maps to the Xp21.3-p22.1 interval, and that the clinical picture in these patients can vary from mild mental retardation to severe ISSX with additional neurological abnormalities. Here, we report a study of two severely affected female patients with apparently de novo balanced X;autosome translocations, both disrupting the serine-threonine kinase 9 (STK9) gene, which maps distal to ARX in the Xp22.3 region. We show that STK9 is subject to X-inactivation in normal female somatic cells and is functionally absent in the two patients, because of preferential inactivation of the normal X. Disruption of the same gene in two unrelated patients who have identical phenotypes (consisting of early-onset severe infantile spasms, profound global developmental arrest, hypsarrhythmia, and severe mental retardation) strongly suggests that lack of functional STK9 protein causes severe ISSX and that STK9 is a second X-chromosomal locus for this disorder.     

Physical fine mapping of the choroideremia locus using Xq21 deletions associated with complex syndromes

Characterization of several male-viable deletions and duplications with 20 random DNA probes has enabled us to subdivide the Xq21 region into seven discernible intervals. Almost all of the deletions spanning part of Xq21 are associated with choroideremia and mental retardation, with deafness being another common feature. The gene locus for choroideremia was assigned to interval 3 spanning the loci DXS95, DXS165, and DXS233. Genes for X-linked deafness and mental retardation were tentatively assigned to interval 2. Deletions of intervals 4 through 7 were not associated with any clinical abnormality. We have constructed a preliminary long-range restriction map of intervals 2 and 3 using field-inversion gel electrophoresis. The DXS232, DXS121, and DXS233 loci are located on the same SfiI fragment, whereas the DXS165 and DXS95 loci could not be linked to this cluster using SfiI and SalI.     

Lowe oculocerebrorenal syndrome in a female with a balanced X;20 translocation: mapping of the X chromosome breakpoint.

A Hispanic girl with Lowe oculocerebrorenal syndrome (OCRL), an X-linked recessive condition characterized by cataracts, glaucoma, mental retardation, and proteinuria, is reported. A balanced X;20 chromosomal translocation with the X chromosome breakpoint at q26.1 was found with high-resolution trypsin-Giemsa banding. Somatic cell hybridization was used to separate the X chromosome derivative and the chromosome 20 derivative in order to position, with respect to the translocation breakpoint, several DNA loci that are linked to the Lowe syndrome locus (Xq24-q26). DXS10 and DXS53 were found to be distal to the breakpoint, whereas DXS37 and DXS42 were located proximal to it. These studies suggest that the OCRL locus lies in the region between these probes. The translocation chromosome originated from an unaffected male without a visible translocation, indicating that the most likely cause of OCRL in this patient is the de novo translocation that disrupted the OCRL locus.     

Assignment of the muscle-eye-brain disease gene to 1p32-p34 by linkage analysis and homozygosity mapping.

Muscle-eye-brain disease (MEB) is an autosomal recessive disease of unknown etiology characterized by severe mental retardation, ocular abnormalities, congenital muscular dystrophy, and a polymicrogyria-pachygyria-type neuronal migration disorder of the brain. A similar combination of muscle and brain involvement is also seen in Walker-Warburg syndrome (WWS) and Fukuyama congenital muscular dystrophy (FCMD). Whereas the gene underlying FCMD has been mapped and cloned, the genetic location of the WWS gene is still unknown. Here we report the assignment of the MEB gene to chromosome 1p32-p34 by linkage analysis and homozygosity mapping in eight families with 12 affected individuals. After a genomewide search for linkage in four affected sib pairs had pinpointed the assignment to 1p, the MEB locus was more precisely assigned to a 9-cM interval flanked by markers D1S200 proximally and D1S211 distally. Multipoint linkage analysis gave a maximum LOD score of 6.17 at locus D1S2677. These findings provide a starting point for the positional cloning of the disease gene, which may play an important role in muscle function and brain development. It also provides an opportunity to test other congenital muscular dystrophy phenotypes, in particular WWS, for linkage to the same locus.     

Concerted evolution led to high expression of a prosimian primate delta globin gene locus

The delta globin gene in simian primates is either weakly expressed (in hominoids and New World monkeys) or silent (in Old World monkeys). In prosimian primates, however, an unequal homologous crossover between the psi eta and delta loci of lemurs produced a hybrid psi eta delta pseudogene locus, whereas in tarsier the delta locus encodes a beta-type chain found in 18% of adult tarsier hemoglobin molecules. In the present study, the nucleotide and amino acid sequences of the galago delta and beta globin genes and their encoded peptides were determined, and evidence is provided showing that the galago delta locus encodes a beta-type chain (beta 2) found in 40% of the galago fetal and postnatal hemoglobin molecules, whereas the beta locus encodes the remaining 60% of the beta-type chain (beta 1). Galago beta 1 and beta 2 chains differ from each other by only one amino acid residue. The homology between the galago delta and beta loci extends from 800 base pairs 5' of the proximal CCAAT element to near the end of exon 3 as a result of a recombination event in which beta sequence replaced delta sequence. After this initial recombination event, concerted evolution between the loci continued over their conserved coding, intron 1, and promoter regions but failed to occur between the two loci in their intron 2 and distal 5'-flanking sequences where the two loci have now diverged by 20%. Calculations based on this divergence value and on a rate of noncoding sequence evolution of 4.2 x 10(-9) to 5.5 x 10(-9) substitutions/site/year for the lorisiform lineage to galago yielded a date of 18-24 million years ago for the initial recombination event. The fact that the promoter sequences of the galago delta locus are the same as that of the galago beta locus may account for the high level of expression of the galago delta gene.     

Molecular investigation of mental retardation locus gene PRSS12 by linkage analysis

The present study was carried out to determine the prevalence of families having mental retardation in Pakistani population. We enrolled seven mentally retarded (MR) families with two or more affected individuals. Family history was taken to minimize the chances of other abnormalities. Pedigrees were drawn using the Cyrillic software (version 2.1). The structure of pedigrees shows that all the marriages are consanguineous and the families have recessive mode of inheritance. All the families were studied by linkage analysis to mental retardation locus (MRT1)/gene PRSS12. Three STR markers (D4S191, D4S2392, and D4S3024) in vicinity of mental retardation (MR) locus (MRT1)/gene PRSS12 were amplified on all the sample of each family by PCR. The PCR products were then genotyped on non denaturing polyacrylamide gel electrophoresis (PAGE). The Haplotype were constructed to determine the pattern of inheritance and also to determine that a family was linked or unlinked to gene PRSS12. One out of the seven families was potentially linked to gene PRSS12, while the other six families remain unlinked.     

Molecular analyses of 17p11.2 deletions in 62 Smith-Magenis syndrome patients.

Smith-Magenis syndrome (SMS) is a clinically recognizable, multiple congenital anomalies/mental retardation syndrome caused by an interstitial deletion involving band p11.2 of chromosome 17. Toward the molecular definition of the interval defining this microdeletion syndrome, 62 unrelated SMS patients in conjunction with 70 available unaffected parents were molecularly analyzed with respect to the presence or absence of 14 loci in the proximal region of the short arm of chromosome 17. A multifaceted approach was used to determine deletion status at the various loci that combined (i) FISH analysis, (ii)PCR and Southern analysis of somatic cell hybrids retaining the deleted chromosome 17 from selected patients, and (iii) genotype determination of patients for whom a parent(s) was available at four microsatellite marker loci and at four loci with associated RFLPs. The relative order of two novel anonymous markers and a new microsatellite marker was determined in 17p11.2. The results confirmed that the proximal deletion breakpoint in the majority of SMS patients is located between markers D17S58 (EW301) and D17S446 (FG1) within the 17p11.1-17p11.2 region. The common distal breakpoint was mapped between markers cCI17-638, which lies distal to D17S71, and cCI17-498, which lies proximal to the Charcot Marie-Tooth disease type 1A locus. The locus D17S258 was found to be deleted in all 62 patients, and probes from this region can be used for diagnosis of the SMS deletion by FISH. Ten patients demonstrated molecularly distinct deletions; of these, two patients had smaller deletions and will enable the definition of the critical interval for SMS.