Dataset Information

Severe Progressive Autism Associated with Two de novo Changes: A 2.6-Mb 2q31.1 Deletion and a Balanced t(14;21)(q21.1;p11.2) Translocation with Long-Range Epigenetic Silencing of LRFN5 Expression.

ABSTRACT: In a 19-year-old severely autistic and mentally retarded girl, a balanced de novo t(14;21)(q21.1;p11.2) translocation was found in addition to a de novo 2.6-Mb 2q31.1 deletion containing 15 protein-encoding genes. To investigate if the translocation might contribute to developmental stagnation at the age of 2 years with later regression of skills, i.e. a more severe phenotype than expected from the 2q31.1 deletion, the epigenetic status and expression of genes proximal and distal to the 14q21.1 breakpoint were investigated in Ebstein Barr Virus-transformed lymphoblast and primary skin fibroblast cells. The 14q21.1 breakpoint was found to be located between a cluster of 7 genes 0.1 Mb upstream, starting with FBXO33, and the single and isolated LRFN5 gene 2.1 Mb downstream. Only expression of LRFN5 appeared to be affected by its novel genomic context. In patient fibroblasts, LRFN5 expression was 10-fold reduced compared to LRFN5 expressed in control fibroblasts. In addition, a relative increase in trimethylated histone H3 lysine 9 (H3K9M3)-associated DNA starting exactly at the translocation breakpoint and going 2.5 Mb beyond the LRFN5 gene was found. At the LRFN5 promoter, there was a distinct peak of trimethylated histone H3 lysine 27 (H3K27M3)-associated DNA in addition to a diminished trimethylated histone H3 lysine 4 (H3K4M3) level. We speculate that dysregulation of LRFN5, a postsynaptic density-associated gene, may contribute to the patient's autism, even though 2 other patients with 14q13.2q21.3 deletions that included LRFN5 were not autistic. More significantly, we have shown that translocations may influence gene expression more than 2 Mb away from the translocation breakpoint.

SUBMITTER: de Bruijn DR

PROVIDER: S-EPMC2883852 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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Publications

Severe Progressive Autism Associated with Two de novo Changes: A 2.6-Mb 2q31.1 Deletion and a Balanced t(14;21)(q21.1;p11.2) Translocation with Long-Range Epigenetic Silencing of LRFN5 Expression.

de Bruijn D R H DR van Dijk A H A AH Pfundt R R Hoischen A A Merkx G F M GF Gradek G A GA Lybæk H H Stray-Pedersen A A Brunner H G HG Houge G G

Molecular syndromology 20100212 1

In a 19-year-old severely autistic and mentally retarded girl, a balanced de novo t(14;21)(q21.1;p11.2) translocation was found in addition to a de novo 2.6-Mb 2q31.1 deletion containing 15 protein-encoding genes. To investigate if the translocation might contribute to developmental stagnation at the age of 2 years with later regression of skills, i.e. a more severe phenotype than expected from the 2q31.1 deletion, the epigenetic status and expression of genes proximal and distal to the 14q21.1 ...[more]

PMID: 20648246

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Project description:Balanced constitutional reciprocal translocations are the most common structural chromosomal rearrangements identiï¬ed in man and pigs. Carriers are generally phenotypically normal, but such rearrangements frequently lead to reproductive disorders. In reciprocal translocation heterozygotes, the homologous regions of the normal and derivative chromosomes involved in the rearrangement pair during the prophase of the first meiotic division, thanks to the synaptonemal complex (SC), and form a particular structure called quadrivalent. In some cases, chromosomal regions (within the quadrivalent) remain unsynapsed, especially around the breakpoints, which may trigger meiosis checkpoints leading to spermatogenesis arrest at the pachytene stage. Several hypotheses have been proposed to explain such effects of pairing failure on gametogenesis. The first one is an altered transcription of the genes located on the unpaired segments. Indeed, studies conducted in mice revealed a transcriptional repression of unpaired regions by a specific mechanism called âMeiotic Silencing of Unsynapsed Chromatinâ (MSUC) in individuals with a partial or total spermatogenesis arrest (Turner et al., 2005). If some genes necessary for the proper course of meiosis are located in such unsynapsed genomic regions, MSUC may result in an arrest of the meiotic division. Secondly, associations between the âquadrivalentâ and the XY bivalent which is transcriptionally silenced by a phenomenon known as meiotic sex chromosome inactivation (MSCI, (Turner, 2007) were also observed in individuals with altered semen parameters (azoospermic or oligospemic) (Oliver-Bonet et al., 2005; Sciurano et al., 2007a, 2012). Such an association could result in a partial reactivation of the XY body (XYB) leading to the expression of some genes located on the X chromosome (Lifschytz and Lindsley, 1972), or result in the spreading of the XYB inactivation towards the autosomal segments attached to the XYB, without reactivation of the latter (Jaafar et al., 1993). Beyond the potential spermatogenesis failure mentioned above, reciprocal translocations are systematically responsible for the production of genetically unbalanced gametes. Here we report the detailed analysis of the whole meiotic process (from spermatocytes to spermatozoa) in the case of a constitutional balanced reciprocal translocation responsible for severe oligoasthenoteratospermia. Total RNA was extracted in 3 replicates from testicular biopsies control animals, from testicular biopsy of an oligospermic boar and from testicular biopsy of a severe oligo-astheno-teratospermic boar carrier of the trcp(1;14) reciprocal translocation.

Project description:Balanced constitutional reciprocal translocations are the most common structural chromosomal rearrangements identiﬁed in man and pigs. Carriers are generally phenotypically normal, but such rearrangements frequently lead to reproductive disorders. In reciprocal translocation heterozygotes, the homologous regions of the normal and derivative chromosomes involved in the rearrangement pair during the prophase of the first meiotic division, thanks to the synaptonemal complex (SC), and form a particular structure called quadrivalent. In some cases, chromosomal regions (within the quadrivalent) remain unsynapsed, especially around the breakpoints, which may trigger meiosis checkpoints leading to spermatogenesis arrest at the pachytene stage. Several hypotheses have been proposed to explain such effects of pairing failure on gametogenesis. The first one is an altered transcription of the genes located on the unpaired segments. Indeed, studies conducted in mice revealed a transcriptional repression of unpaired regions by a specific mechanism called “Meiotic Silencing of Unsynapsed Chromatin” (MSUC) in individuals with a partial or total spermatogenesis arrest (Turner et al., 2005). If some genes necessary for the proper course of meiosis are located in such unsynapsed genomic regions, MSUC may result in an arrest of the meiotic division. Secondly, associations between the “quadrivalent” and the XY bivalent which is transcriptionally silenced by a phenomenon known as meiotic sex chromosome inactivation (MSCI, (Turner, 2007) were also observed in individuals with altered semen parameters (azoospermic or oligospemic) (Oliver-Bonet et al., 2005; Sciurano et al., 2007a, 2012). Such an association could result in a partial reactivation of the XY body (XYB) leading to the expression of some genes located on the X chromosome (Lifschytz and Lindsley, 1972), or result in the spreading of the XYB inactivation towards the autosomal segments attached to the XYB, without reactivation of the latter (Jaafar et al., 1993). Beyond the potential spermatogenesis failure mentioned above, reciprocal translocations are systematically responsible for the production of genetically unbalanced gametes. Here we report the detailed analysis of the whole meiotic process (from spermatocytes to spermatozoa) in the case of a constitutional balanced reciprocal translocation responsible for severe oligoasthenoteratospermia.

Dataset Information

Severe Progressive Autism Associated with Two de novo Changes: A 2.6-Mb 2q31.1 Deletion and a Balanced t(14;21)(q21.1;p11.2) Translocation with Long-Range Epigenetic Silencing of LRFN5 Expression.

Publications

Severe Progressive Autism Associated with Two de novo Changes: A 2.6-Mb 2q31.1 Deletion and a Balanced t(14;21)(q21.1;p11.2) Translocation with Long-Range Epigenetic Silencing of LRFN5 Expression.

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