X-linked dominant chondrodysplasia with platyspondyly, distinctive brachydactyly, hydrocephaly, and microphthalmia

Chassaing, Nicolas; Siani, Virginie; Carles, Dominique; Delezoïde, Anne Lise; Alberti, Eve Marie; Battin, J; Chateil, Jean‐François; Gilbert‐Dussardier, Brigitte; Coupry, Isabelle; Arveiler, Benoı̂t; Saura, R.; Lacombe, Didier

doi:10.1002/ajmg.a.30570

Cited by 12 publications

(4 citation statements)

References 14 publications

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“…Our data, supported by the known functions of HDAC6 and other HDACs, in particular HDAC4, another class II HDAC, strongly suggest that we have probably identified the molecular cause of the new form of X-linked chondrodysplasia that we previously described (2). This would represent to our knowledge the first example of a developmental disease caused by the abrogation of the post-transcriptional regulation normally exerted by a microRNA on its target gene.…”

Section: Discussionsupporting

confidence: 76%

A mutation in the 3′-UTR of the HDAC6 gene abolishing the post-transcriptional regulation mediated by hsa-miR-433 is linked to a new form of dominant X-linked chondrodysplasia

Simon¹,

Laloo

Barillot³

et al. 2010

Human Molecular Genetics

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A family with dominant X-linked chondrodysplasia was previously described. The disease locus was ascribed to a 24 Mb interval in Xp11.3-q13.1. We have identified a variant (c.*281A>T) in the 3' untranslated region (UTR) of the HDAC6 gene that totally segregates with the disease. The variant is located in the seed sequence of hsa-miR-433. Our data showed that, in MG63 osteosarcoma cells, hsa-miR-433 (miR433) down-regulated both the expression of endogenous HDAC6 and that of an enhanced green fluorescent protein-reporter mRNA bearing the wild-type 3'-UTR of HDAC6. This effect was totally abrogated when the reporter mRNA bore the mutated HDAC6 3'-UTR. The HDAC6 protein was found to be over-expressed in thymus from an affected male fetus. Concomitantly, the level of total alpha-tubulin, a target of HDAC6, was found to be increased in the affected fetal thymus, whereas the level of acetylated alpha-tubulin was found to be profoundly decreased. Skin biopsies were obtained from a female patient who presented a striking body asymmetry with hypotrophy of the left limbs. The mutated HDAC6 allele was expressed in 31% of left arm-derived fibroblasts, whereas it was not expressed in the right arm. Overexpression of HDAC6 was observed in left arm-derived fibroblasts. Altogether these results strongly suggest that this HDAC6 3'-UTR variant suppressed hsa-miR-433-mediated post-transcriptional regulation causing the overexpression of HDAC6. This variant is likely to constitute the molecular cause of this new form of X-linked chondrodysplasia. This represents to our knowledge the first example of a skeletal disease caused by the loss of a miRNA-mediated post-transcriptional regulation on its target mRNA.

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Section: Discussionsupporting

confidence: 76%

A mutation in the 3′-UTR of the HDAC6 gene abolishing the post-transcriptional regulation mediated by hsa-miR-433 is linked to a new form of dominant X-linked chondrodysplasia

Simon¹,

Laloo

Barillot³

et al. 2010

Human Molecular Genetics

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“…Additionally, a hemizygous deletion of HDAC9 has been identified in a small proportion of schizophrenia patients [137]. Moreover, mutations in the 3′ untranslated regions (UTR) of HDAC6 , which encodes the class IIB KDAC enzyme, suppress miR433-mediated posttranscriptional regulation and cause overexpression of HDAC6 , resulting in chondrodysplasia with platyspondyly, distinctive brachydactyly, hydrocephaly, and microphtalmia syndrome (OMIM 300863), which exhibits, among other symptoms, hydrocephaly and macrocephaly [138], [139]. Taken together, these findings suggest an essential role of KDACs during brain development in humans and argue for distinct functions of different KDACs during this process.…”

Section: Human Disorders Caused By Abnormalities In Kat or Kdac Activitymentioning

confidence: 99%

Lysine Acetylation and Deacetylation in Brain Development and Neuropathies

Tapias

Wang

2017

Genomics, Proteomics &Amp; Bioinformatics

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Embryonic development is critical for the final functionality and maintenance of the adult brain. Brain development is tightly regulated by intracellular and extracellular signaling. Lysine acetylation and deacetylation are posttranslational modifications that are able to link extracellular signals to intracellular responses. A wealth of evidence indicates that lysine acetylation and deacetylation are critical for brain development and functionality. Indeed, mutations of the enzymes and cofactors responsible for these processes are often associated with neurodevelopmental and psychiatric disorders. Lysine acetylation and deacetylation are involved in all levels of brain development, starting from neuroprogenitor survival and proliferation, cell fate decisions, neuronal maturation, migration, and synaptogenesis, as well as differentiation and maturation of astrocytes and oligodendrocytes, to the establishment of neuronal circuits. Hence, fluctuations in the balance between lysine acetylation and deacetylation contribute to the final shape and performance of the brain. In this review, we summarize the current basic knowledge on the specific roles of lysine acetyltransferase (KAT) and lysine deacetylase (KDAC) complexes in brain development and the different neurodevelopmental disorders that are associated with dysfunctional lysine (de)acetylation machineries.

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“…Chondrodysplasia is caused by alterations in the extracellular matrix of the cartilage or defects in the differentiation and proliferation of chondrocytes. Chassaing et al (Chassaing et al 2005) reported a new form of X-linked dominant chondrodysplasia that is different from the other X-linked types of chondrodysplasia, such as CDPX1, CDPX2 and CHILD syndrome. Affected males exhibit severe phenotypes that include platyspondyly, hydrocephaly, facial dysmorphism and microphtalmia, whereas affected females show less severe phenotypes, namely small stature with variable expression of body asymmetry and mental retardation (Chassaing et al 2005).…”

Section: A Mutation In the Mir-433-binding Site Of The Hdac6 Gene Assmentioning

confidence: 99%

“…Chassaing et al (Chassaing et al 2005) reported a new form of X-linked dominant chondrodysplasia that is different from the other X-linked types of chondrodysplasia, such as CDPX1, CDPX2 and CHILD syndrome. Affected males exhibit severe phenotypes that include platyspondyly, hydrocephaly, facial dysmorphism and microphtalmia, whereas affected females show less severe phenotypes, namely small stature with variable expression of body asymmetry and mental retardation (Chassaing et al 2005). Subsequently, the same group identified an A-to-T mutation in the 3'UTR of the Histone deacetylase 6 (HDAC6) gene that is present in all the affected members of the family (Simon et al 2010).…”

Section: A Mutation In the Mir-433-binding Site Of The Hdac6 Gene Assmentioning

confidence: 99%

Human diseases caused by germline and somatic abnormalities in microRNA and microRNA‐related genes

Kawahara

2014

Congenital Anomalies

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The human genome harbors approximately2000 genes that encode microRNAs (miRNAs), small noncoding RNAs of approximately 20-22 nt that mediate posttranscriptional gene silencing. MiRNAs are generated from long transcripts through stepwise processing by the Drosha/ DGCR8, Exportin-5/RanGTP and Dicer/TRBP complexes. Given that the expression of each individual miRNA is tightly regulated, the altered expression of certain miRNAs plays a pivotal role in human diseases. For instance, germline and somatic mutations in the genes encoding the miRNA processing machinery have been reported in different cancers. Furthermore, certain miRNA genes are encoded within regions that are deleted or duplicated in individuals with chromosomal abnormalities, and the fact that the knockout of these miRNAs in animal models results in lethality or the abnormal development of certain tissues indicates that these miRNA genes contribute to the disease phenotypes. It has also been reported that mutations in miRNA genes or in miRNA-binding sites, which result in the impairment of tight regulation of target mRNA expression, cause human genetic diseases, although these cases are rare. This is in contrast to the aberrant expression of certain miRNAs that results from the impairment of transcriptional or post-transcriptional regulation, which has been reported frequently in various human diseases. The present review focuses on human diseases caused by mutations in genes encoding miRNAs and the miRNA processing machinery as well as in miRNA-binding sites. Furthermore, human diseases caused by chromosomal abnormalities that involve the deletion or duplication of regions harboring genes that encode miRNAs or the miRNA processing machinery are also introduced.

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X-linked dominant chondrodysplasia with platyspondyly, distinctive brachydactyly, hydrocephaly, and microphthalmia

Cited by 12 publications

References 14 publications

A mutation in the 3′-UTR of the HDAC6 gene abolishing the post-transcriptional regulation mediated by hsa-miR-433 is linked to a new form of dominant X-linked chondrodysplasia

A mutation in the 3′-UTR of the HDAC6 gene abolishing the post-transcriptional regulation mediated by hsa-miR-433 is linked to a new form of dominant X-linked chondrodysplasia

Lysine Acetylation and Deacetylation in Brain Development and Neuropathies

Human diseases caused by germline and somatic abnormalities in microRNA and microRNA‐related genes

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