guion de radio

European Journal of Human Genetics, 2007

A screen for TBX1 gene mutations identified two mutations in patients with some features compatible with the 22q11.2-deletion syndrome but with no deletions. One is a de novo missense mutation and the other is a 5 0 untranslated region (5 0 UTR) C4T change that affects a nucleotide with a remarkable trans-species conservation. Computer modelling shows that the 5 0 UTR change is likely to affect the mRNA structure and in vitro translation experiments demonstrate that it produces a twofold increase in translation efficiency. Recently, duplications in the 22q11.2 region were reported in patients referred for fragile-X determination because of cognitive and behavioural problems. Because the 5 0 UTR nucleotide change may be a functional equivalent of a duplication of the TBX1 gene, we decided to screen 200 patients who had been referred for fragile-X determination and 400 healthy control individuals. As a result, we found the 5 0 UTR mutation to be present in three patients with mental retardation or behavioural problems and absent in control individuals of the same ethnic background. This observation suggests that it may be reasonable to screen for such mutation among patients with unspecific cognitive deficits and we provide an easy and quick way to do it with an amplification refractory mutation system (ARMS) approach. To our knowledge, this is the first human mutation showing that TBX1 is a candidate causing mental retardation associated with the 22q11.2 duplication syndrome.

American Journal of Medical Genetics, 2004

Journal of Medical Genetics, 1993

Fragile X (fra(X)) syndrome, the most common form of familial mental retardation, is caused by heritable unstable DNA composed of CGG repeats. As reproductive fitness of fra(X) patients is severely compromised, a high mutation rate has been proposed to explain the high prevalence. However, we have been unable to show any new mutation for 84 probands referred to us to date. We show here the same fra(X) gene in five fra(X) probands with common ancestors married in 1747. The lack of new fra(X) mutations implies that there must be many more fra(X) gene carriers in the population than previously realised. As it is now possible to detect asymptomatic fra(X) gene carriers by DNA analysis, extended family studies for any new proband are recommended. A family illustrating the importance of fra(X) carriership determination is reported. (J Med Genet 1993;30:94-6)

Genetics in Medicine, 2001

DergiPark (Istanbul University), 2007

Objectives: The fragile X syndrome (FXS) is the most frequent cause of inherited mental retardation (MR). It is caused by the progressive expansion of (CGG)n trinucleotide repeats located in the promoter region of the (Fragile X mental retardation 1 gene) FMR1 gene at Xq27.3. The aim of the study is to estimate the prevalance of the FXS and other chromosomal aberrations by cytogenetic and molecular analysis in patients with MR and language disorders. Material and Method: 72 cases with MR who were sent to our laboratory for molecular and cytogenetic search in term of fragile X. The lymphocyte culture was carried out according to standard methods. DNA extraction was done using whole blood DNA extraction kit (Bangalore Genei, Bangalore). This was followed by bisulphite treatment and PCR amplification. Results: Chromosome abnormality was found in 12 cases (16.7%). 7 cases (9.7%) were detected fragile X positive in molecular analysis. The mutations were detected such a full mutation and abnormal methylation in (4.1%) and a premutation carrier (5.5%). We concluded that chromosomal studies in mentally retarded patients help in accurate diagnosis and proper prognosis followed by genetic counseling and management rehabilitation. Conclusion: Due to recent molecular advances, our understanding of the perplexing genetic issues surrounding fragile X syndrome has grown and diagnostic techniques have become both reliable and readily available.

Nucleic Acids Research, 1991

The fragile X syndrome is an X-linked disorder which has been shown to be associated with the length variation of a DNA fragment containing a CGG trinucleotide repeat element at or close to the fragile site. Phenotypically normal carriers of the disorder generally have a smaller length variation than affected individuals. We have cloned the region in cosmids and defined the area containing the amplified sequence. We have used probes from the region to analyse the mutation in families. We show that the mutation evolves in different ways in different individuals of the same family. In addition we show that not all fragile X positive individuals show this amplification of DNA sequence even though they show expression of the fragile site at levels greater than 25%. One patient has alterations in the region adjacent to the CGG repeat elements. Three patients in fragile X families have the normal fragment with amplification in a small population of their cells. These observations indicate that there is molecular heterogeneity in the fragile X syndrome and that the DNA fragment length variation is not the only sequence responsible for the expression of the fragile site or the disease phenotype.

The Journal of Molecular Diagnostics, 2005

Several diagnostic strategies have been applied to the detection of FMR1 gene repeat expansions in fragile X syndrome. Here, we report a novel polymerase chain reaction-based strategy using the Expand Long Template PCR System (Roche Diagnostics, Mannheim, Germany) and the osmolyte betaine. Repeat expansions up to ϳ330 CGGs in males and up to at least ϳ160 CGGs in carrier women could be easily visualized on ethidium bromide agarose gels. We also demonstrated that fluorescence analysis of polymerase chain reaction products was a reliable tool to verify the presence of premutation and full mutation alleles both in males and in females. This technique, primarily designed to detect premutation alleles, can be used as a routine first screen for expanded FMR1 alleles.

European Journal of Medical Genetics, 2007

Mental retardation affects 2 to 3% of the population and is marked by significant etiological heterogeneity, including genetic and non genetic causes. FRAXA (FMR1) trinucleotide expansion is widely searched in routine screening, but found in only about 2% of the patients tested. Mutations of the MECP2 (methyl-CpG-binding protein) gene mainly cause Rett syndrome but were also shown to be involved in mental retardation. This study aimed to estimate the frequency of MECP2 gene mutations in a large group of mentally retarded patients without FRAXA expansion. Screening by heteroduplex analysis and SSCP followed by DNA sequencing of shifted bands were performed on 613 patients, including 442 males and 171 females. Eleven sequence variants were found, including nine polymorphisms. The two others may be pathogenetic. The first one, the double nucleotide substitution c.1162_1163delinsTA leading to a premature stop codon (p.Pro388X) was found in a female patient with random X-inactivation, presenting with borderline mental impairment without any features of Rett syndrome. The second one, the c.679C>G substitution, changing a glutamine to a glutamate in the transcriptional repression functional domain (p.Gln227Glu), was found in a female patient with a moderately biased X-chromosome inactivation profile and presenting with mild intellectual delay and minor psychotic features. The low

American Journal of Medical Genetics Part A, 2006

The ARX gene mutations have been demonstrated to cause different forms of mental retardation (MR). Beside FMR1, in families with X-linked mental retardation (XLMR), the ARX dysfunction was demonstrated to be among the most frequent causes of this heterogeneous group of disorders. Nevertheless, in sporadic cases of MR, ARX mutations are extremely rare. In order to evaluate the frequency of ARX mutation in XLMR, we performed mutational analysis of ARX in 165 mentally retarded probands negative for FRAXA and belonging to families in which the condition segregates as an X-linked condition. The same recurrent mutation, an in frame 24 bp insertion (c.428-451dup (24 bp)), was identified in five patients. In one family, the mother of two affected boys was found not to carry the mutation detected in her sons. These data suggest the presence of germline mosaicism for the mutation in the mother. Our results confirm the significant contribution of ARX mutations in the etiology of MR, especially in this group of patients selected for XLMR (3%). These data, together with those reported in the literature, imply that screening for c.428-451 dup (24 bp) mutation should be recommended in all patients with suspected XLMR. ß 2006 Wiley-Liss, Inc.

International Journal of Pediatric Otorhinolaryngology, 2012