Duplications of noncoding elements 5′ of SOX9 are associated with brachydactyly-anonychia

Kurth, Ingo; Klopocki, Eva; Stricker, Sigmar; Oosterwijk, Jolieke G. van; Vanek, Sebastian; Altmann, Jens; Santos, Heliosa G; Harssel, J. J. T. van; Ravel, Thomy de; Wilkie, Andrew O.M.; Gal, Andreas; Mundlos, Stefan

doi:10.1038/ng0809-862

Cited by 103 publications

(86 citation statements)

References 5 publications

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“…Of note, however, full mirror-image polydactyly was only present in the fetuses with larger genomic aberrations and therefore we cannot fully exclude that other genes in the deleted genomic region might cause, or at least influence this particular phenotype. As there is increasing evidence that copy number changes in non-coding genomic elements are implicated in bone disorders, 18,19 deletions of non-coding regulatory elements upstream or downstream of PITX1 might also account for the clinical variability observed.…”

Section: Discussionmentioning

confidence: 99%

Deletions in PITX1 cause a spectrum of lower-limb malformations including mirror-image polydactyly

Klopocki

Kähler²,

Foulds

et al. 2012

Eur J Hum Genet

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PITX1 is a bicoid-related homeodomain transcription factor implicated in vertebrate hindlimb development. Recently, mutations in PITX1 have been associated with autosomal-dominant clubfoot. In addition, one affected individual showed a polydactyly and right-sided tibial hemimelia. We now report on PITX1 deletions in two fetuses with a high-degree polydactyly, that is, mirror-image polydactyly. Analysis of DNA from additional individuals with isolated lower-limb malformations and higher-degree polydactyly identified a third individual with long-bone deficiency and preaxial polydactyly harboring a heterozygous 35 bp deletion in PITX1. The findings demonstrate that mutations in PITX1 can cause a broad spectrum of isolated lower-limb malformations including clubfoot, deficiency of long bones, and mirror-image polydactyly.

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Section: Discussionmentioning

confidence: 99%

Deletions in PITX1 cause a spectrum of lower-limb malformations including mirror-image polydactyly

Klopocki

Kähler²,

Foulds

et al. 2012

Eur J Hum Genet

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“…Recent studies have shown how mutations affecting the structure and integrity of RLs can led to spurious enhancer-promoter contacts (Figure 1 A similar situation is found in duplications of the KCNJ2-SOX9 genomic region, which are associated to the Cook syndrome [20]. A study using a mouse model reproducing this duplication shows that this rearrangement generates a new TAD that expose the When did this topology appear during evolution?…”

Section: Rl Restructuring In Disease and Developmentmentioning

confidence: 92%

Cis-regulatory landscapes in development and evolution

Maeso

Acemel

Gómez-Skármeta

2017

Current Opinion in Genetics & Development

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The recent advances in our understanding of the 3D organization of the chromatin together with an almost unlimited ability to detect cis-regulatory elements genome-wide using different biochemical signatures has provided us with an unprecedented power to study gene regulation. It is now possible to profile the complete regulatory apparatus controlling the spatio-temporal expression of any given gene, the so-called gene Regulatory Landscapes (RLs). Here we review several studies over the last two years demonstrating the functional consequences of altering RL structure in development, disease and evolution. These works clearly shows that a deep understanding of transcriptional regulation is no longer conceivable without considering the 3D modular organization of animal genomes.

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“…[21][22][23] Thus, we also considered genes flanking the SRO as potentially responsible for the abnormal phenotypes.…”

Section: Discussionmentioning

confidence: 99%

Genotype–phenotype relationship in three cases with overlapping 19p13.12 microdeletions

et al. 2010

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We describe the detailed clinical and molecular characterization of three patients (aged 7, 8 4/12 and 31 years) with overlapping microdeletions in 19p13.12, extending to 19p13.13 in two cases. The patients share the following clinical features with a recently reported 10-year-old girl with a 19p13.12 microdeletion: mental retardation (MR), psychomotor and language delay, hearing impairment, brachycephaly, anteverted nares and ear malformations. All patients share a 359-kb deleted region in 19p13.12 harboring six genes (LPHN1, DDX39, CD97, PKN1, PTGER1 and GIPC1), several of which may be MR candidates because of their function and expression pattern. LPHN1 and PKN1 are the most appealing; LPHN1 for its interaction with Shank family proteins, and PKN1 because it is involved in a variety of functions in neurons, including cytoskeletal organization. Haploinsufficiency of GIPC1 may contribute to hearing impairment for its interaction with myosin VI. A behavioral phenotype was observed in all three patients; it was characterized by overactive disorder associated with MR and stereotyped movements (ICD10) in one patient and hyperactivity in the other two. As Ptger1-null mice show behavioral inhibition and impulsive aggression with defective social interaction, PTGER1 haploinsufficiency may be responsible for the behavioral traits observed in these patients.

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Duplications of noncoding elements 5′ of SOX9 are associated with brachydactyly-anonychia

Cited by 103 publications

References 5 publications

Deletions in PITX1 cause a spectrum of lower-limb malformations including mirror-image polydactyly

Deletions in PITX1 cause a spectrum of lower-limb malformations including mirror-image polydactyly

Cis-regulatory landscapes in development and evolution

Genotype–phenotype relationship in three cases with overlapping 19p13.12 microdeletions

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