A novel X-linked gene, DDP, shows mutations in families with deafness (DFN-1), dystonia, mental deficiency and blindness.

In 1960, progressive sensorineural deafness (McKusick 304,700, DFN-1) was shown to be X-linked based on a description of a large Norwegian pedigree. More recently, it was shown that this original DFN-1 family represented a new type of recessive neurodegenerative syndrome characterized by postlingual progressive sensorineural deafness as the first presenting symptom in early childhood, followed by progressive dystonia, spasticity, dysphagia, mental deterioration, paranoia and cortical blindness. This new disorder, termed Mohr-Tranebjaerg syndrome (referred to here as DFN-1/MTS) was mapped to the Xq21.3-Xq22 region2. Using positional information from a patient with a 21-kb deletion in chromosome Xq22 and sensorineural deafness along with dystonia, we characterized a novel transcript lying within the deletion as a candidate for this complex syndrome. We now report small deletions in this candidate gene in the original DFN-1/MTS family, and in a family with deafness, dystonia and mental deficiency but not blindness. This gene, named DDP (deafness/ dystonia peptide), shows high levels of expression in fetal and adult brain. The DDP protein demonstrates striking similarity to a predicted Schizosaccharomyces pombe protein of no known function. Thus, is it likely that the DDP gene encodes an evolutionarily conserved novel polypeptide necessary for normal human neurological development.

Identification of each human chromosome with a modified Giemsa stain.

Differential staining of human chromosomes can be obtained when the pH of Giemsa stain is changed to 9.0 from the usual 6.8. Such staining permits identification of all homolog pairs and distinct regions within chromosome arms. In most instances, the pattern is quite similar to that obtained with quinacrine mustard fluorescence staining. Certain regions, such as the paracentric constrictions in chromosomes Al and C9, and the distal end of the long arm of the Y chromosome stain differently with the Giemsa 9 technique. The technique is considerably simpler than the quinacrine mustard fluorescence technique and identification of homologs is also easier than in cells stained by the latter.

Chromosomal abnormalities in the human population: estimation of rates based on New Haven newborn study.

The incidence of gross chromosomal abnormality was measured in a large (4500), relatively unbiased sample of New Haven infants born during 1 year. The frequency of infants with abnormal chromosomal constitutions was 0.5 percent. For mothers over age 34, 1.5 percent of newborns were chromosomally abnormal. Only one in four of these infants could have been detected by phenotypic criteria alone. Methods are discussed whereby this fraction of the newborn population might be detected and possibly reduced.

Specific reading disability: identification of an inherited form through linkage analysis.

Linkage analysis in families with apparent autosomal dominant reading disability produced a lod score of 3.241. Since the traditionally accepted significance level for linkage is a lod score of 3.0, these results strongly suggest that a gene playing a major etiologic role in one form of reading disability is on chromosome 15.

Genetic polymorphisms of human mitochondrial glutamic oxaloacetic transaminase.

In a survey of 860 unselected human placental extracts, three variants of mitochondrial glutamic oxaloacetic transaminase were found, all of which were common enough to be considered polymorphisms. Family studies showed that this enzyme is under the control of nuclear rather than mitochondrial DNA.

Golabi-Ito-Hall syndrome results from a missense mutation in the WW domain of the PQBP1 gene.

BACKGROUND: Golabi, Ito, and Hall reported a family with X linked mental retardation (XLMR), microcephaly, postnatal growth deficiency, and other anomalies, including atrial septal defect, in 1984. METHODS: This family was restudied as part of our ongoing study of XLMR, but significant linkage to X chromosome markers could not be found. Extreme short stature and microcephaly as well as other new clinical findings were observed. Mutations in the polyglutamine tract binding protein 1 gene (PQBP1) have recently been reported in four XLMR disorders (Renpenning, Hamel cerebro-palato-cardiac, Sutherland-Haan, and Porteous syndromes) as well as in several other families. The clinical similarity of our family to these patients with mutations in PQBP1, particularly the presence of microcephaly, short stature, and atrial septal defect, prompted examination of this gene. RESULTS: A missense mutation in PQBP1 was identified which changed the conserved tyrosine residue in the WW domain at position 65 to a cysteine (p.Y65C). CONCLUSIONS: This is the first missense mutation identified in PQBP1 and the first mutation in the WW domain of the gene. The WW domain has been shown to play an important role in the regulation of transcription by interacting with the PPxY motif found in transcription factors. The p.Y65C mutation may affect the proper functioning of the PQBP1 protein as a transcriptional co-activator.

A new X linked mental retardation (XLMR) syndrome with short stature, small testes, muscle wasting, and tremor localises to Xq24-q25.

METHODS: A large family is described in which mental retardation segregates as an X linked trait. Six affected males in three generations were studied by linkage and clinical examination. RESULTS: Characteristic clinical features include short stature, prominent lower lip, small testes, muscle wasting of the lower legs, kyphosis, joint hyperextensibility, abnormal gait, tremor, and decreased fine motor coordination. Affected subjects also had impaired speech and decreased attention span. A carrier female was mildly affected. A similar disorder was not found on review of our XLMR Database of 124 syndromes. Linkage analysis of 37 markers resulted in a lod score of 2.80 at DXS1212 and 2.76 at DXS425. The limiting markers were DXS424 and DXS1047. Ten of 124 XLMR syndromes and eight of 58 MRX families overlap this region. CONCLUSIONS: In summary, this family appears to have a new XLMR syndrome localising to Xq24-q25.

Temporal lobe surface area measurements on MRI in normal and dyslexic readers.

In a neuroanatomical study of dyslexia, measurements were made of the superior surface of the temporal lobe (SSTL) on MRI scans in a sample of 17 dyslexics and 21 non-dyslexic subjects. Both anterior and posterior halves of the SSTL area showed significant leftward asymmetry in non-dyslexics, but showed symmetry in dyslexics. The total SSTL area showed greater leftward asymmetry in non-dyslexics than in dyslexics. The dyslexics also revealed a significant correlation (r = 0.69, P = 0.005) between Woodcock-Johnson Passage Comprehension scores and posterior SSTL asymmetry, such that those with higher scores had more leftward asymmetry. This suggests that among dyslexics the direction of SSTL asymmetry may serve as a risk factor and/or a marker for the severity of reading comprehension problems.

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.

A large kindred with X-linked mental retardation, marker X and macroorchidism.

Thirty-eight members of a black kindred with mental retardation and the Marker X were studied. Ten of 14 affected males, 6 of 6 affected females, 18 carriers or possible carriers, and 7 normal males were examined. Eight of 9 affected males who could be measured had macroorchidism, but their ears and mandibles were not prominent. No distinct facies were evident, although minor anomalies, such as a slight pectus, were present in some. Clinical diagnosis in the absence of a strongly positive family history may be even more difficult among prepubertal black children than in whites. The risk of retardation among children of carriers was estimated at 20-40%.

Size and pericentric inversion heteromorphisms of secondary constriction regions (h) of chromosomes 1, 9, and 16 as detected by CBG technique in Caucasians: classification, frequencies, and incidence.

Eighty normal Caucasians were studied by CBG technique for estimation of size and inversion heteromorphisms of chromosomes 1, 9, and 16. Size heteromorphisms were classified into one of five sizes using 16p as a reference standard: very small, small, intermediate, large, and very large. Inversion heteromorphisms were also classified into 5 categories - eg, no inversion; partial inversion - minor; half inversion; partial inversion - major; and complete inversion. The frequencies of size heteromorphisms for chromosomes 1, 9, and 16 were 11.3%, 47.5%, and 7.5%, respectively. Thirty-four chromosomes were found to have inversions. Of these, 16 were in chromosome 1, and 18 were in chromosome 9. No inversions were found in chromosome 16. An increase in the size of the h region was more frequently associated with inversion, suggesting that there is a possible relationship between size and inversion. For example, there were 118 chromosomes that were classified as "intermediate" by size; 23 (19.5%) had inversions. In contrast, there were 225 that were "small" in size, and only 10 (4.4%) had inversions. There was no significant difference between males and females for size and position heteromorphisms.

Restudy of the original marker X family.

Restudy of the original marker-X family confirmed recent observations that this XLMR disorder is associated with large testes and slightly abnormal ears. However, other aspects of the phenotype were variable and a distinct facies was not evident. Significant differences in marker-X frequency between two laboratories processing the same samples were observed. Possibly, the combination of more cells and a longer culture time in one laboratory led to a greater depletion of critical nutrients and a higher frequency of the marker-X, but additional studies are needed. No evidence was found of a diminishing frequency of the marker-X over a 15 year period.

A form of X-linked mental retardation with marfanoid habitus.

A kindred has been studied in which mental retardation and marfanoid clinical features are present in several individuals. The pedigree is consistent with X-linked recessive inheritance. Four affected males aged 12-18 years and four obligate carriers have been identified. Clinical findings in the 4 affected males included a tall slender habitus (3) (the fourth was tall but muscular), a long-narrow face (3), large head (4), highly arched palate (4), small mandible (4), abnormal speech (4), hypernasal voice (3), joint hyperextensibility (3), borderline to large testes (3), pectus excavatum (2), atrial septal defect (1), and a double row of teeth (1). Mental retardation (4) ranged from mild to severe; abnormal behavior included hyperactive and aggressive behavior (2), autistic-like (1) and jovial behavior (1). One and possibly two, males had absence of the corpus callosum. Chromosome studies on all were normal; no marker X was observed. We believe this family probably represents a new form of X-linked mental retardation.

XLMR genes: update 1990.

We have identified 39 X-linked conditions in which mental retardation seems to be the primary characteristic, although pathogenesis is unknown. These conditions can be subdivided into syndromal and non-syndromal, depending on the existence of a recognizable pattern of minor anomalies and/or malformations, or lack thereof. Seventeen genes have been regionally mapped onto the X chromosome. However, in 14 instances the data were derived from a single family and most lod scores were less than 3.0.

Nomenclature guidelines for X-linked mental retardation.

Nomenclature guidelines are proposed for non-specific and for syndromal forms of X-linked mental retardation. Non-specific mental retardations (MRX) are given unique symbols for each family (MRX1, MRX2, MRX3 ...). Syndromal mental retardations (MRXS) which do not as yet have specific symbols are given unique interim symbols for each syndrome (MRXS1, MRXS2, MRXS3 ...). The prerequisite for assignment of serial MRX and MRXS gene symbols is a minimum lod score (or multipoint lod score) of +2 between the MR locus and one or more X chromosome markers. Prior approval of availability for proposed gene symbols must be obtained from the Nomenclature Committee of the Human Gene Mapping Workshops.

XLMR genes: update 1994.

We provide a comprehensive list of all known forms of X-linked mental retardation. It comprises 127 entries, subdivided into 5 categories (syndromes, dominant disorders, metabolic disorders, neuromuscular disorders, and nonspecific mental retardation). Map location of 69 putative loci demonstrates several overlaps, which will only be resolved by more refined mapping or cloning of the respective genes. The ultimate goal of identifying all the genes on the X chromosome whose mutations cause mental retardation will require a concerted effort between clinical and molecular investigators.

XLMR genes: update 1998.

Since the Seventh Fragile X and XLMR Mental Retardation (XLMR) Workshop in 1995, the genes for Coffin-Lowry, Mohr-Tranebjaerg, and Opitz G/BBB syndromes have been cloned. Jensen syndrome has been found to be allelic to Mohr-Tranebjaerg. Twenty new XLMR syndromes and metabolic or neuromuscular disorders have been reported. Twenty-four new localizations have been established, including five in previously reported conditions (FG, Carpenter, Arts, OPA2, and OFD1). The number of families with nonspecific XLMR that have been reported has continued to increase; 58 families or loci are now known. Eighteen new families with nonspecific mental retardation (MRX) have been reported. Two of them, however, were subsequently found to have mutations in the RABGDIA gene, which codes for a GDP-dissociation inhibitor for RAB proteins. In total, 41 more entries have been added to the X chromosome map of XLMR. The total number of known syndromes and MRX families has increased to 178. Of the 120 known XLMR disorders, 53 have been mapped, and 22 have been cloned. Assuming that at least 10 loci are necessary to account for the 58 families with MRX, the total number of XLMR loci counted so far would be 130. Although it is likely that many of the disorders will eventually prove to be allelic, it is not possible at present to determine the precise number of loci for nonspecific XLMR.

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.

XLMR genes: update 1996.

A current list of all known forms of X-linked mental retardation (XLMR) and a slightly revised classification are presented. The number of known disorders has not increased because 6 disorders have been combined based on new molecular data or on clinical grounds and only 6 newly described XLMR disorders have been reported. Of the current 105 XLMR disorders, 34 have been mapped, and 18 disorders and 1 nonspecific XLMR (FRAXE) have been cloned. The number of families with nonspecific XLMR with a LOD score of > or = 2.0 has more than doubled, with 42 (including FRAXE) now being known. a summary of the localization of presumed nonspecific mental retardation (MR) genes from well-studied X-chromosomal translocations and deletions is also included. Only 10-12 nonoverlapping loci are required to explain all localizations of nonspecific MR from both approaches. These new trends mark the beginning of a significantly improved understanding of the role of genes on the X chromosome in producing MR. Continued close collaboration between clinical and molecular investigators will be required to complete the process.

Study of X-linked mental retardation (XLMR): summary of 61 families in the Miami/Greenwood Study.

The initial goal of this study was to localize as many genes as possible that lead to syndromic and nonspecific XLMR. More recently, this goal has been redefined to include narrowing these localizations and cloning specific genes. In the last 5 years, 61 families have participated in this study; 34 have a projected or actual lod score greater than 2.0. Restudy of 12 families reported previously has been a particularly productive aspect of this study and has led to clinical redefinition and new or improved localization of most of these syndromes. Five possible new XLMR syndromes have been identified. Five large families with nonspecific XLMR have been regionally localized. Since many XLMR conditions are based on only 1 or 2 family reports, one of the major purposes of this summary is to provide clinical data on the study families so that collaborative projects can be undertaken with other centers that have similar families.