Position effect in human genetic disease

Kleinjan, Dirk-Jan; Heyningen, Veronica van

doi:10.1093/hmg/7.10.1611

Cited by 342 publications

(255 citation statements)

References 84 publications

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“…This is suggested by the location of the breakpoint at the 5 0 position of the gene, as is observed in most instances where position effects are encountered. 24 Moreover, the finding of a normal expression of another gene located in the vicinity of the amisyn gene, argues against a more general silencing mechanism imposed on the entire region. The alteration of the chromatin structure is postulated to be accompanied by altered DNA methylation and post-translational histone modifications.…”

Section: Translocation Position Effectmentioning

confidence: 99%

Position effect leading to haploinsufficiency in a mosaic ring chromosome 14 in a boy with autism

et al. 2008

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We describe an individual with autism and a coloboma of the eye carrying a mosaicism for a ring chromosome consisting of an inverted duplication of proximal chromosome 14. Of interest, the ring formation was associated with silencing of the amisyn gene present in two copies on the ring chromosome and located at 300 kb from the breakpoint. This observation lends further support for a locus for autism on proximal chromosome 14. Moreover, this case suggests that position effects need to be taken into account, when analyzing genotype -phenotype correlations based on chromosomal imbalances.

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Section: Translocation Position Effectmentioning

confidence: 99%

Position effect leading to haploinsufficiency in a mosaic ring chromosome 14 in a boy with autism

et al. 2008

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“…35,36 The mechanism that may cause such effects are: (1) separation of the gene from its enhancer or promoter region, (2) removal of the longrange insulator or boundary element, (3) competition with another enhancer, (4) juxtaposition with an enhancer element from another gene and (5) position -effect variegation, that is the insertion of the gene in a new heterochromatin environment.…”

Section: Discussionmentioning

confidence: 99%

Two patients with balanced translocations and autistic disorder: CSMD3 as a candidate gene for autism found in their common 8q23 breakpoint area

et al. 2008

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Recent studies estimated a rate of 3-5% of cytogenetic abnormalities involving many different chromosomes in autistic spectrum disorders (ASDs). Here, we report on two unrelated male patients with de novo translocations, autistic behaviour and psychomotor delay. These two patients carry a balanced chromosome translocation t(5;8)(q14.3;q23.3) and t(6;8)(q13;q23.2), respectively. A detailed physical map covering the regions involved in the translocations was constructed using BAC clones mapping on chromosomes 5q14.3, 6q13 and 8q23. Fluorescence in situ hybridisation (FISH) analyses were carried out using these genomic clones. We fine mapped the two translocation breakpoints on chromosomes 8 identifying their position within a short 5 Mb genomic region. Breakpoints on chromosomes 8 in both patients do not interrupt any known gene but both map in a region containing the CSMD3 gene, which thereby can be considered as a candidate for ASDs.

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“…Chromosomal translocations that disrupt the regulatory information or cause position affects are well known for SHH [11], as well as for many other genes [12]. These SHH chromosomal lesions usually result in holoprosencephaly; however, we recently reported a patient with additional malformations displaying severe syndactyly (fusion of the digits) of the hands and feet.…”

Section: Regulatory Mutations Cause Congenital Abnormalitiesmentioning

confidence: 99%

Alterations to the remote control ofShhgene expression cause congenital abnormalities

Hill

Lettice

2013

Phil. Trans. R. Soc. B

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Multi-species conserved non-coding elements occur in the vertebrate genome and are clustered in the vicinity of developmentally regulated genes. Many are known to act as cis -regulators of transcription and may reside at long distances from the genes they regulate. However, the relationship of conserved sequence to encoded regulatory information and indeed, the mechanism by which these contribute to long-range transcriptional regulation is not well understood. The ZRS, a highly conserved cis -regulator, is a paradigm for such long-range gene regulation. The ZRS acts over approximately 1 Mb to control spatio-temporal expression of Shh in the limb bud and mutations within it result in a number of limb abnormalities, including polydactyly, tibial hypoplasia and syndactyly. We describe the activity of this developmental regulator and discuss a number of mechanisms by which regulatory mutations in this enhancer function to cause congenital abnormalities.

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Position effect in human genetic disease

Cited by 342 publications

References 84 publications

Position effect leading to haploinsufficiency in a mosaic ring chromosome 14 in a boy with autism

Position effect leading to haploinsufficiency in a mosaic ring chromosome 14 in a boy with autism

Two patients with balanced translocations and autistic disorder: CSMD3 as a candidate gene for autism found in their common 8q23 breakpoint area

Alterations to the remote control ofShhgene expression cause congenital abnormalities

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