Long-term effectiveness and generality of practical functional assessment and skill-based treatment.

There are several considerations to address when conducting functional communication training for challenging behavior in a school setting, such as the need for schedule thinning and maintenance across staff and the need to establish a variety of appropriate classroom skills. There are several strategies for conducting schedule thinning following functional communication training and for transferring effects across people or settings. However, there are few examples of these processes in natural settings with relevant caregivers and with long-term maintenance of effects.

MG132-induced progerin clearance is mediated by autophagy activation and splicing regulation.

Hutchinson-Gilford progeria syndrome (HGPS) is a lethal premature and accelerated aging disease caused by a point mutation in encoding A-type lamins. Progerin, a truncated and toxic prelamin A issued from aberrant splicing, accumulates in HGPS cells' nuclei and is a hallmark of the disease. Small amounts of progerin are also produced during normal aging.

Splicing-directed therapy in a new mouse model of human accelerated aging.

Hutchinson-Gilford progeria syndrome (HGPS) is caused by a point mutation in the LMNA gene that activates a cryptic donor splice site and yields a truncated form of prelamin A called progerin. Small amounts of progerin are also produced during normal aging. Studies with mouse models of HGPS have allowed the recent development of the first therapeutic approaches for this disease.

A naturally occurring human minidysferlin protein repairs sarcolemmal lesions in a mouse model of dysferlinopathy.

Dysferlinopathies are autosomal recessive, progressive muscle dystrophies caused by mutations in DYSF, leading to a loss or a severe reduction of dysferlin, a key protein in sarcolemmal repair. Currently, no etiological treatment is available for patients affected with dysferlinopathy. As for other muscular dystrophies, gene therapy approaches based on recombinant adeno-associated virus (rAAV) vectors are promising options.

Immunolabelling and flow cytometry as new tools to explore dysferlinopathies.

Dysferlinopathies are autosomal recessive muscular dystrophies caused by DYSF mutations, which lead to a reduced amount or a complete lack of dysferlin. One step in dysferlinopathies diagnosis consists in Western blot analysis of proteins extracted from muscle biopsy, or blood monocytes. We have taken advantage of dysferlin expression in monocytes to develop a whole blood flow cytometry (WBFC), using antibodies directed against dysferlin.

In human pachytene spermatocytes, SUMO protein is restricted to the constitutive heterochromatin.

SUMO-1, a ubiquitin-like protein, is covalently bound to many proteins, leading to chromatin inactivation and transcriptional repression. The high concentration of SUMO-1 on the XY body in rodents suggests that this protein has an important role in facultative heterochromatin organization. In human, the precise role of SUMO in chromatin/heterochromatin organization remains to be defined.

Recurrent rearrangements in the proximal 15q11-q14 region: a new breakpoint cluster specific to unbalanced translocations.

Unbalanced translocations, that involve the proximal chromosome 15 long arm and the telomeric region of a partner chromosome, result in a karyotype of 45 chromosomes with monosomy of the proximal 15q imprinted region. Here, we present our analysis of eight such unbalanced translocations that, depending on the parental origin of the rearranged chromosome, were associated with either Prader-Willi or Angelman syndrome. First, using FISH with specific BAC clones, we characterized the chromosome 15 breakpoint of each translocation and demonstrate that four of them are clustered in a small 460 kb interval located in the proximal 15q14 band.

PML nuclear bodies are highly organised DNA-protein structures with a function in heterochromatin remodelling at the G2 phase.

We have recently demonstrated that heterochromatin HP1 proteins are aberrantly distributed in lymphocytes of patients with immunodeficiency, centromeric instability and facial dysmorphy (ICF) syndrome. The three HP1 proteins accumulate in one giant body over the 1qh and 16qh juxtacentromeric heterochromatins, which are hypomethylated in ICF. The presence of PML (promyelocytic leukaemia) protein within this body suggests it to be a giant PML nuclear body (PML-NB).

Screening for subtelomeric rearrangements using automated fluorescent genotyping of microsatellite markers: a Lebanese study.

A screening for submicroscopic rearrangements using specific polymorphic microsatellite markers from the subtelomeric regions of all chromosome arms was performed in 34 independent Lebanese families, including 45 patients with idiopathic mental retardation plus additional features. Five cryptic rearrangements were found in five different families, but subsequent FISH studies confirmed only three of those, showing a proportion of nearly 9% of subtelomeric rearrangements in our population. Two patients presented a de novo deletion from paternal origin, one involving telomere 3p, and another telomere 7p.

SRPX2 mutations in disorders of language cortex and cognition.

The rolandic and sylvian fissures divide the human cerebral hemispheres and the adjacent areas participate in speech processing. The relationship of rolandic (sylvian) seizure disorders with speech and cognitive impairments is well known, albeit poorly understood. We have identified the Xq22 gene SRPX2 as being responsible for rolandic seizures (RSs) associated with oral and speech dyspraxia and mental retardation (MR).

Mutation in the 5' alternatively spliced region of the XNP/ATR-X gene causes Chudley-Lowry syndrome.

The Chudley-Lowry syndrome (ChLS, MIM 309490) is an X-linked recessive condition characterized by moderate to severe mental retardation, short stature, mild obesity, hypogonadism, and distinctive facial features characterized by depressed nasal bridge, anteverted nares, inverted-V-shaped upper lip, and macrostomia. The original Chudley-Lowry family consists of three affected males in two generations. Linkage analysis had localized the gene to a large interval, Xp21-Xq26 and an obligate carrier was demonstrated to have highly skewed X inactivation.

Subcellular distribution of HP1 proteins is altered in ICF syndrome.

The Immunodeficiency, Centromeric instability, and Facial (ICF) syndrome is a rare autosomal recessive disorder that results from mutations in the DNMT3B gene, encoding a DNA-methyltransferase that acts on GC-rich satellite DNAs. This syndrome is characterized by immunodeficiency, facial dysmorphy, mental retardation of variable severity and chromosomal abnormalities that essentially involve juxtacentromeric heterochromatin of chromosomes 1 and 16. These abnormalities demonstrate that hypomethylation of satellite DNA can induce alterations in the structure of heterochromatin.

Disruption of a new X linked gene highly expressed in brain in a family with two mentally retarded males.

Background: Mental retardation (MR) affects 2-3% of the human population and some of these cases are genetically determined. Although several genes responsible for MR have been identified, many cases have still not been explained.

Methods: We have identified a pericentric inversion of the X chromosome inv(X)(p22.

TSPY, the candidate gonadoblastoma gene on the human Y chromosome, has a widely expressed homologue on the X - implications for Y chromosome evolution.

TSPY, a candidate gene for a factor that promotes gonadoblastoma formation (GBY), is a testis-specific multicopy gene family in the male-specific region of the human Y (MSY) chromosome. Although it was originally proposed that male-specific genes on the Y originated from a transposed copy of an autosomal gene (Lahn & Page 1999b), at least two male-specific genes (RBMY and SRY) descended from a formerly recombining X-Y identical gene pair. Here we show that a TSPY homologue with similar gene structure lies in conserved positions, close to SMCX, on the X chromosome in human (TSPX ) and mouse (Tspx).

HP1beta and HP1gamma, but not HP1alpha, decorate the entire XY body during human male meiosis.

During meiosis in male mammals, the X and Y chromosomes become heterochromatic and transcriptionally silent, and form the XY body. Although the HP1 proteins are known to be involved in the packaging of chromosomal DNA into repressive heterochromatin domains, their involvement in facultative heterochromatinization has not been precisely determined. Here, we analyse, for the first time in humans, the subcellular distribution of the heterochromatin protein HP1alpha, HP1beta and HP1gamma isoforms, in male pachytene spermatocytes, and the XY body facultative heterochromatin in particular.

Mechanism of intrachromosomal triplications 15q11-q13: a new clinical report.

We describe here a patient with intrachromosomal triplication 15q11-q13, a rare chromosomal event associated with severe mental retardation and intractable epilepsy. Cytogenetic studies including FISH on interphasic nuclei showed that the middle segment of the triplication was inverted in orientation. Molecular analyses demonstrated that the rearrangement was of maternal origin.

A human interstitial telomere associates in vivo with specific TRF2 and TIN2 proteins.

Mammalian telomeres are composed of long arrays of TTAGGG repeats that form a nucleoprotein complex which protects the chromosome ends. Human telomere function is known to require two TTAGGG repeat factors, TRF1 and TRF2, and several interacting proteins, but the mechanism by which the DNA/protein complex prevents end to end fusion in vivo has not been elucidated. In order to better understand the role of specific telomere-associated proteins in the organisation of chromosome ends, we have studied a patient with a rare chromosome rearrangement that has given rise to an interstitial telomere.

Abnormal expression of the KLF8 (ZNF741) gene in a female patient with an X;autosome translocation t(X;21)(p11.2;q22.3) and non-syndromic mental retardation.

Non-syndromic X linked mental retardation (MRX) is a heterogeneous group of conditions in which all patients have mental retardation as the only constant phenotypic feature. We have identified a female patient with mental retardation and a balanced translocation involving chromosomes X and 21, t(X;21)(p11.2;q22.

Wdr12, a mouse gene encoding a novel WD-Repeat Protein with a notchless-like amino-terminal domain.

The WD-repeat protein family consists of a large group of structurally related yet functionally diverse proteins found predominantly in eukaryotic cells. These factors contain several (4-16) copies of a recognizable amino-acid sequence motif (the WD unit) thought to be organized into a "propeller-like" structure involved in protein-protein regulatory interactions. Here, we report the cloning of a mouse cDNA, referred to as Wdr12, which encodes a novel WD-repeat protein of 423 amino acids.

Organization of the X and Y chromosomes in human, chimpanzee and mouse pachytene nuclei using molecular cytogenetics and three-dimensional confocal analyses.

We used multicolour fluorescence in-situ hybridization on air-dried pachytene nuclei to analyse the structural and functional domains of the sex vesicle (SV) in human, chimpanzee and mouse. The same technology associated with 3-dimensional analysis was then performed on human and mouse pachytene nuclei from cytospin preparations and tissue cryosections. The human and the chimpanzee SVs were very similar, with a consistently small size and a high degree of condensation.

ATR-X mutations cause impaired nuclear location and altered DNA binding properties of the XNP/ATR-X protein.

Mutations in the XNP/ATR-X gene, located in Xq13.3, are associated with several X linked mental retardation syndromes, the best known being alpha thalassaemia with mental retardation (ATR-X). The XNP/ATR-X protein belongs to the family of SWI/SNF DNA helicases and contains three C2-C2 type zinc fingers of unknown function.