Fragile X chromosome and X-linked mental retardation.

A family is described in which three normal females transmitted to seven males X-linked mental retardation associated with macro-orchidism and a fragile site on the long arm of the X chromosome -- fra(X)(q27). The affected males also had minor clinical features in common: a large forehead, long face, large ears, a long upper lip and large extremities.     

Some problems in the genetics of X-linked mental retardation

X-linked mental retardation has recently become one of the most interesting genetic anomalies. Studying this group of conditions has led to many insights into the mechanisms involved in normal and abnormal gene actions in humans. Since the early 1980s, the number of disease entities for which the responsible genes could be localized on the X chromosome has increased from year to year; at the Ninth International Workshop on Fragile-X-Syndrome and X-linked Mental Retardation, 199 such disease units were counted (Hamel, 1999). Conventionally, these units were subdivided into two groups: syndromal and non-syndromal types. The syndro- mal types are characterized by external features, neurological signs, and/or metabolic anomalies. The non-syndromal types do not show such specific features; here, the X-linked mode of inheritance is the only indicator. Due to the reduced reproduction of mentally severely retarded males, a relatively high fraction of new mutants among cases of a specific type must be expected. It cannot be the purpose of the present short article to review sufficiently well the entire field; this would require a complete book. Rather, it is our intention to point to some open problems and possible ways for their solution.     

X-linked mental retardation

X-linked mental retardation (XLMR) affects 1.8 per thousand male births and is usually categorized as "syndromic" (MRXS) or "non-specific" (MRX) forms according to the presence or absence of specific signs in addition to the MR. Up to 60 genes have been implicated in XLMR and certain mutations can alternatively lead to MRXS or MRX. Indeed the extreme phenotypic and allelic heterogeneity of XLMR makes the classification of most genes difficult. Therefore, following identification of new genes, accurate retrospective clinical evaluation of patients and their families is necessary to aid the molecular diagnosis and the classification of this heterogeneous group of disorders. Analyses of the protein products corresponding to XLMR genes show a great diversity of cellular pathways involved in MR. Common mechanisms are beginning to emerge : a first group of proteins belongs to the Rho and Rab GTPase signaling pathways involved in neuronal differentiation and synaptic plasticity and a second group is related to the regulation of gene expression. In this review, we illustrate the complexity of XLMR conditions and present recent data about the FMR1, ARX and Oligophrenin 1 genes.     

X-linked mental retardation

Genetic factors have an important role in the aetiology of mental retardation. However, their contribution is often underestimated because in developed countries, severely affected patients are mainly sporadic cases and familial cases are rare. X-chromosomal mental retardation is the exception to this rule, and this is one of the reasons why research into the genetic and molecular causes of mental retardation has focused almost entirely on the X-chromosome. Here, we review the remarkable recent progress in this field, its promise for understanding neural function, learning and memory, and the implications of this research for health care.     

X-linked non-specific mental retardation

Non-specific mental retardation is a very common and genetically heterogeneous disorder but, to date, only six genes related to this condition have been identified. Five of these six have been found in the past two years, through positional-cloning efforts of mapped X-linked families. The characteristics of the newly identified genes are providing insights into the molecular mechanisms of mental impairment and the development of cognitive functions.     

X-linked mental retardation and epigenetics

The search for the genetic defects in constitutional diseases has so far been restricted to direct methods for the identification of genetic mutations in the patients' genome. Traditional methods such as karyotyping, FISH, mutation screening, positional cloning and CGH, have been complemented with newer methods including array-CGH and PCR-based approaches (MLPA, qPCR). These methods have revealed a high number of genetic or genomic aberrations that result in an altered expression or reduced functional activity of key proteins. For a significant percentage of patients with congenital disease however, the underlying cause has not been resolved strongly suggesting that yet other mechanisms could play important roles in their etiology. Alterations of the 'native' epigenetic imprint might constitute such a novel mechanism. Epigenetics, heritable changes that do not rely on the nucleotide sequence, has already been shown to play a determining role in embryonic development, X-inactivation, and cell differentiation in mammals. Recent progress in the development of techniques to study these processes on full genome scale has stimulated researchers to investigate the role of epigenetic modifications in cancer as well as in constitutional diseases. We will focus on mental impairment because of the growing evidence for the contribution of epigenetics in memory formation and cognition. Disturbance of the epigenetic profile due to direct alterations at genomic regions, or failure of the epigenetic machinery due to genetic mutations in one of its components, has been demonstrated in cognitive derangements in a number of neurological disorders now. It is therefore tempting to speculate that the cognitive deficit in a significant percentage of patients with unexplained mental retardation results from epigenetic modifications.     

Further delineation of X-linked mental retardation

Summary Chromosomal, clinical, and psychological data are presented on members of six families with X-linked mental retardation. Affected males in three of these families express the fra(X)(q28) marker, while the retarded males in the other three do not. Similar variable physical and psychological charateristics, such as lop ears, large testes, and perseverative speech, are present in affected males in all six families. Preliminary analysis of the psychological data also shows that males with and without marker expression cannot be differentiated with certainty. On this basis we suggest that there is a type of X-linked mental retardation with many phenotypic features of marker-X mental retardation but without expression of the X chromosome fragile site.     

Monogenic causes of X-linked mental retardation

Mutations in X-linked genes are likely to account for the observation that more males than females are affected by mental retardation. Causative mutations have recently been identified in both syndromic X-linked mental retardation (XLMR) and in the genetically heterogeneous 'nonspecific' forms of XLMR, for which cognitive impairment is the only defining clinical feature. Proteins that function in chromatin remodelling are affected in three important syndromic forms of XLMR. In nonspecific forms of the disorder, defects have been found in signal-transduction pathways that are believed to function during neuronal maturation. These findings provide important insights into the molecular and cellular defects that underlie mental retardation.     

The frequency of X-linked mental retardation

600 mentally retarded children, 339 boys and 261 girls aged 5-9 years were examined. Boys to girls ratio (B:G) was found in the total group to be 1.3. Among 257 children with mental retardation of confirmed genetic origin B:G = 1.4, in 129 children with confirmed exogenous defects B:G = 1.04. The significant prevalence of boys over girls was characteristic of children with monogenic forms. The frequency of X-linked mental retardation in the total group, in all mentally retarded boys and in boys with genetic forms was 12.5 +/- 1.3%, 22.1 +/- 2.2% and 28.5 +/- 2.8%, respectively. The frequency of X-linked mental retardation was higher in boys with genetic forms of imbecility.     

细胞信号转导与X连锁的非特异性精神发育迟滞

非特异性精神发育迟滞是患者仅表现出一般或特殊认知功能障碍的一种病症。对相关的基因及其生理功能进行研究,不仅对弄清非特异性精神发育迟滞的遗传基础有重要意义,还能揭示人类认知功能的分子遗传机理。文章对一些涉及X连锁的非特异精神发育迟滞的基因,其表达产物同时参与细胞信号转导的信号分子,如跨膜受体、鸟苷酸相关蛋白和激酶的生理功能及其研究现状进行了阐述,揭示了细胞信号转导与人类认知活动之间的密切关系,为精神发育迟滞的治疗或预防提供新思路。     

Chromosome X-linked mental retardation and marfanoid syndrome

In the present paper we report two pairs of slightly to moderately mentally retarded brothers with Marfanoid habitus and similar craniofacial changes. They had a long and narrow face, small mandible, high-arched palate and hypernasal voice, as previously reported by Lujan et al. (1984) in 4 mentally retarded males of a large kindred. The present data suggest the existence of a specific type of X-linked mental retardation with Marfanoid habitus.     

Chromosome characteristics of X-linked mental retardation. II. Autosomes

The frequencies of chromosome and chromatid breaks and gaps were studied in blood lymphocytes of three groups of individuals: 21 males with X-linked mental retardation characterized by fragile X chromosome; 52 males with non-differentiated X-linked mental retardation having no fra(X) chromosome in their cells; 15 intellectually normal males. The lymphocytes were cultured both in medium 199 and in Eagle's medium supplemented with fluoro-deoxyuridine. The significantly higher frequencies of various autosomal lesions were observed in the individuals with the fragile X chromosome syndrome and in those with mental retardations without fra(X) chromosome, in comparison with normal males. The significant difference in some autosome lesions was also found between both groups of the patients. The distribution of chromosome lesions in autosomes of different groups was significantly higher in chromosomes A and lower in groups B, E, F and G, than expected in accordance with their relative length in the haploid set. In all the groups of individuals studied, the predominant localization of chromosome and chromatid breaks and gaps was observed in fragile sites 1p31, 3p14, 6q26 and 16q23.     

A nuclear role for the Fragile X mental retardation protein.

Fragile X syndrome results from lack of expression of a functional form of Fragile X mental retardation protein (FMRP), a cytoplasmic RNA-binding protein of uncertain function. Here, we report that FMRP contains a nuclear export signal (NES) that is similar to the NES recently identified in the Rev regulatory protein of human immunodeficiency virus type 1 (HIV-1). Mutation of this FMRP NES results in mis-localization of FMRP to the cell nucleus. The FMRP NES is encoded within exon 14 of the FMR1 gene, thus explaining the aberrant nuclear localization of a natural isoform of FMRP that lacks this exon. The NES of FMRP can substitute fully for the Rev NES in mediating Rev-dependent nuclear RNA export and specifically binds a nucleoporin-like cellular cofactor that has been shown to mediate Rev NES function. Together, these findings demonstrate that the normal function of FMRP involves entry into the nucleus followed by export via a pathway that is identical to the one utilized by HIV-1 Rev. In addition, these data raise the possibility that FMRP could play a role in mediating the nuclear export of its currently undefined cellular RNA target(s).     

Molecular basis of X-linked non-specific mental retardation

Mental retardation (MR) is a common disorder, affecting 1-3% of the total population. This condition results from failure to develop cognitive abilities and intelligence level appropriate for the age group. Mental retardation is basically a clinically as well as etiologically heterogeneous type of condition and both genetic and non-genetic factors have been found to be involved. There are more than 1000 entries in Online Mendelian Inheritance in Man (OMIM) database under the name of mental retardation. In recent years 15 genes for X linked non-specific mental retardation have been identified which provide important clues regarding molecular and cellular processes involved in signal transduction cascade in central nervous system. Recent advancements in identification and characterization of X-linked non-specific mental retardation genes have been discussed in this review. Understanding of the molecular pathways of disease causing genes would be helpful in developing effective therapeutic approaches for mental retardation.     

Linkage mapping of a severe X-linked mental retardation syndrome.

A four-generation Swedish family with a new type of X-linked mental retardation syndrome was recently reported by Gustavson et al. The complex syndrome includes microcephaly, severe mental retardation, optical atrophy with decreased vision or blindness, severe hearing defect, characteristic facial features, spasticity, seizures, and restricted joint motility. The patients die during infancy or early in childhood. Twenty-one family members, including two affected males, were available for study. Linkage analysis was conducted in the family by using 11 RFLP markers and 10 VNTR markers spread along the X chromosome. A hypervariable short tandem repeat of DXS294 at Xq26 showed a peak two-point lod score of 3.35 at zero recombination fraction. Calculations using the same markers revealed a multipoint peak lod score of 3.65 at DXS294. Crossover events with the centromeric marker DXS424 and the telomeric marker DXS297 delimit a probable region for the gene localization. It is noteworthy that hte disease loci of two other syndromes with overlapping clinical manifestations recently were shown by Turner et al. and Pettigrew et al. to be linked to markers at Xq26.     

Making an impression on X-linked mental retardation

Oligophrenin-1 encodes a rhoGAP protein involved in X-linked mental retardationBilluart, P. (1998)Nature 392, 923–926PAK3 mutation in nonsyndromic X-linked mental retardationAllen, K.M. et al. (1998)Nat. Genet. 20, 25–30Mutations in GDI1 are responsible for X-linked non-specific mental retardationD'Adamo, P. et al. (1998)Nat. Genet. 19, 134–139Non-specific X-linked semidominant mental retardation by mutations in a Rab GDP-dissociation inhibitorBienvenu, T. et al. (1998)Hum. Mol. Genet. 7, 1311–1315     

Fragile (X) X-linked mental retardation. II. Frequency and replication pattern of fragile (X)(q28) in heterozygotes

The frequency of cytologic expression and the replication pattern of the fragile (X) [fra(X)] were investigated in 28 fra(X) heterozygotes, of which 25 agreed to psychological assessment. One-third of the heterozygotes in this study are mentally retarded. The intellectually impaired carriers had a higher frequency of fra(X) and a higher proportion of early-replicating fra(X) than the normally intelligent carriers. The early-replicating fra(X) accounted for 39% of the variability in IQ and the late-replicating fra(X) for 12%. Age had a minimal inverse effect on fra(X) expression and replication pattern. Thus, it appears that mental retardation in females heterozygous for the fra(X) may largely be a function of the proportion of cells with an early-replicating, active X chromosome possessing the fragile site.     

A new form of X-linked mental retardation with growth retardation, deafness, and microgenitalism.

The proband and two maternal uncles were similarly affected by a unique constellation of mental retardation and physical abnormalities. There were severe retardation, growth less than the third percentile, and significantly delayed bone age. They manifested deafness, a flat nasal bridge, several ocular abnormalities, and a rudimentary scrotum with cryptorchidism, and one had a small penis. The proband also had onychodystrophy of his fingers and toes. Their birth weights and lengths were less than expected. No chromosomal or biochemical abnormality was detected. Both uncles died, but the proband is healthy at 4 years. Their phenotype is distinguished from other forms of X-linked mental retardation and appears to be a new syndrome.