{'fraction_non_alphanumeric': 0.03592181722134179, 'fraction_numerical': 0.024300052826201797, 'mean_word_length': 4.739393939393939, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 1, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
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 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.