Sequence variation in ultraconserved and highly conserved elements does not cause X‐linked mental retardation

Chelly, Jamel; Brouwer, Arjan P.M. de; Pardo, B.; Barker, Mandy; Capra, Valeria; Bartoloni, Lucia; Antonarakis, Stylianos E.; Conrad, Bernard

doi:10.1002/ajmg.a.31651

Cited by 5 publications

(3 citation statements)

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“…KANSL1 is a member of the evolutionarily conserved nonspecific lethal (NSL) complex that controls various cellular functions, including transcription regulation and stem cell identity maintenance and reprogramming[ 16 , 17 ]. The NSL complex contains the histone acetyltransferase MOF (males absent on the first) encoded by KAT8 which acetylates histone H4 on lysine 16 (H4K16) and with lower efficiency on lysines 5 and 8 (H4K5 and H4K8, respectively) to facilitate transcriptional activation[ 18 , 19 ]. Recent studies in flies have shown that KANSL1 acts as a scaffold protein interacting with four NSL subunits including WDR5 which plays a critical role in assembling distinct histone-modifying complexes with different epigenetic regulatory functions[ 20 ].…”

Section: Introductionmentioning

confidence: 99%

Mouse models of 17q21.31 microdeletion and microduplication syndromes highlight the importance of Kansl1 for cognition

et al. 2017

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Koolen-de Vries syndrome (KdVS) is a multi-system disorder characterized by intellectual disability, friendly behavior, and congenital malformations. The syndrome is caused either by microdeletions in the 17q21.31 chromosomal region or by variants in the KANSL1 gene. The reciprocal 17q21.31 microduplication syndrome is associated with psychomotor delay, and reduced social interaction. To investigate the pathophysiology of 17q21.31 microdeletion and microduplication syndromes, we generated three mouse models: 1) the deletion (Del/+); or 2) the reciprocal duplication (Dup/+) of the 17q21.31 syntenic region; and 3) a heterozygous Kansl1 (Kans1+/-) model. We found altered weight, general activity, social behaviors, object recognition, and fear conditioning memory associated with craniofacial and brain structural changes observed in both Del/+ and Dup/+ animals. By investigating hippocampus function, we showed synaptic transmission defects in Del/+ and Dup/+ mice. Mutant mice with a heterozygous loss-of-function mutation in Kansl1 displayed similar behavioral and anatomical phenotypes compared to Del/+ mice with the exception of sociability phenotypes. Genes controlling chromatin organization, synaptic transmission and neurogenesis were upregulated in the hippocampus of Del/+ and Kansl1+/- animals. Our results demonstrate the implication of KANSL1 in the manifestation of KdVS phenotypes and extend substantially our knowledge about biological processes affected by these mutations. Clear differences in social behavior and gene expression profiles between Del/+ and Kansl1+/- mice suggested potential roles of other genes affected by the 17q21.31 deletion. Together, these novel mouse models provide new genetic tools valuable for the development of therapeutic approaches.

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Section: Introductionmentioning

confidence: 99%

Mouse models of 17q21.31 microdeletion and microduplication syndromes highlight the importance of Kansl1 for cognition

et al. 2017

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“…The majority of tested UCEs are expressed in the central and peripheral nervous systems ( Bejerano et al 2006 ; Pennacchio et al 2006 ). A few preliminary attempts to link mutations in UCEs to human neural disorders, including multiple sclerosis, mental retardation, and autism have been unsuccessful, thus raising the question of the importance of these elements in the proper expression and function of their surrounding genes ( Ban et al 2005 ; Richler et al 2006 ; Bottani et al 2007 ).…”

Section: Introductionmentioning

confidence: 99%

Widespread Ultraconservation Divergence in Primates

Ovcharenko

2008

Molecular Biology and Evolution

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The distribution and evolution of ultraconserved elements (UCEs, DNA stretches that are perfectly identical in primates and rodents) were examined in genomes of 3 primate species (human, chimpanzee, and rhesus macaque). It was found that the number of UCEs has decreased throughout primate evolution. At least 26% of ancestral UCEs have diverged in hominoids, whereas an additional 17% have accumulated one or more single nucleotide polymorphisms in the human genome. Sequence polymorphism analyses indicate that mutation fixation within an UCE can trigger a relaxation in the selective constraint on that element. Homogeneous mutation accumulations in UCEs served as a template by which purifying selection acted more effectively on protein-coding UCEs. Gene ontology annotation suggests that UCE sequence variation, primarily occurring in noncoding regions, might be linked to the reprogramming of the expression pattern of transcription factors and developmentally important genes. Many of these genes are expressed in the central nervous system. Finally, UCE sequence variability within human populations has been identified, including population-specific nonsynonymous changes in protein-coding regions.

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“…Studies have shown that nonexonic elements tend to be organized in clusters near transcription factors and developmental genes, whereas the exonic elements are enriched in genes involved in RNA binding and regulation of splicing. Accumulative evidence suggested the important function of UCEs involving in DNA binding, RNA processing, the regulation of transcription, and the development of diseases [6][7][8][9]. Using microarray analysis, Calin et al [10] first reported that a large fraction of non-coding UCEs are in fact transcribed (so-called transcribed UCEs (T-UCEs)), and have expression levels in a tissue-specific manner and deregulate in human cancers.…”

Section: Introductionmentioning

confidence: 99%

Genetic variants in ultraconserved elements and risk of breast cancer in Chinese population

Shen

Lü

Jiang

et al. 2011

Breast Cancer Res Treat

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Ultraconserved elements (UCEs) are the most extreme representatives of conserved non-coding sequences. Recent studies have indicated that UCEs are not mutation cold regions and likely to be concerned with cancers, including breast cancer (BC). In this study, we first screened common single-nucleotide polymorphisms (SNPs) (minor allele frequency, MAF > 0.05) in Chinese population located in 481 UCEs sequences and selected seven SNPs (rs17049105, rs13020355, rs2682406, rs2056116, rs11190870, rs9572903, and rs8004379) of uc.51, uc.82, uc.133, uc.140, uc.302, uc.353, and uc.368, respectively. A two-stage case-control study of BC with a total of 1,497 cases and 1,497 controls in Chinese population was conducted to test the hypothesis that these SNPs of UCEs are associated with BC risk. Stage I with 735 cases and 735 controls was designed to discover the risk variants, followed by stage II with 762 cases and 762 controls to validate the significant variants. In stage I, although the genotype distributions of all seven SNPs were not significantly different between BC cases and controls, logistic regression analyses revealed that the variant genotypes of rs8004379 were significantly associated with the increased risk of BC (dominant model: adjusted OR = 1.27, 95% CI = 1.01-1.58, P = 0.039). We then selected two SNPs, rs8004379 A/C and rs2056116 A/G, with lowest P values of the associations into the stage II analysis. However, none of above two SNPs were significantly associated with BC risk in both stage II and pooled set (rs8004379 AC/CC vs. AA: adjusted OR = 0.88, 95% CI = 0.68-1.13 for stage II and adjusted OR = 1.09, 95% CI = 0.92-1.29 for the pooled set; rs2056116 AG/GG vs. AA: adjusted OR = 1.12, 95% CI = 0.87-1.45 for stage II and adjusted OR = 1.11, 95% CI = 0.94-1.31 for the pooled set). These findings did not support a significant association between UCEs SNPs and the risk of BC in Chinese population.

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Sequence variation in ultraconserved and highly conserved elements does not cause X‐linked mental retardation

Cited by 5 publications

References 10 publications

Mouse models of 17q21.31 microdeletion and microduplication syndromes highlight the importance of Kansl1 for cognition

Mouse models of 17q21.31 microdeletion and microduplication syndromes highlight the importance of Kansl1 for cognition

Widespread Ultraconservation Divergence in Primates

Genetic variants in ultraconserved elements and risk of breast cancer in Chinese population

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