{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,9]],"date-time":"2025-11-09T07:00:54Z","timestamp":1762671654578},"reference-count":57,"publisher":"The Company of Biologists","issue":"8","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2003,4,15]]},"abstract":"<jats:p>The 5\u2032 members of the Hoxa and Hoxd gene clusters play major roles in vertebrate limb development. One such gene, HOXD13, is mutated in the human limb malformation syndrome synpolydactyly. Both polyalanine tract expansions and frameshifting deletions in HOXD13 cause similar forms of this condition, but it remains unclear whether other kinds of HOXD13mutations could produce different phenotypes. We describe a six-generation family in which a novel combination of brachydactyly and central polydactyly co-segregates with a missense mutation that substitutes leucine for isoleucine at position 47 of the HOXD13 homeodomain. We compared the HOXD13(I47L) mutant protein both in vitro and in vivo to the wild-type protein and to an artificial HOXD13 mutant, HOXD13(IQN), which is completely unable to bind DNA. We found that the mutation causes neither a dominant-negative effect nor a gain of function, but instead impairs DNA binding at some sites bound by wild-type HOXD13. Using retrovirus-mediated misexpression in developing chick limbs, we showed that wild-type HOXD13 could upregulate chick EphA7in the autopod, but that HOXD13(I47L) could not. In the zeugopod, however,HOXD13(I47L) produced striking changes in tibial morphology and ectopic cartilages, which were never produced by HOXD13(IQN), consistent with a selective rather than generalised loss of function. Thus, a mutant HOX protein that recognises only a subset of sites recognised by the wild-type protein causes a novel human malformation, pointing to a hitherto undescribed mechanism by which missense mutations in transcription factors can generate unexpected phenotypes. Intriguingly, both HOXD13(I47L) and HOXD13(IQN)produced more severe shortening in proximal limb regions than did wild-type HOXD13, suggesting that functional suppression of anterior Hox genes by more posterior ones does not require DNA binding and is mediated by protein:protein interactions.<\/jats:p>","DOI":"10.1242\/dev.00396","type":"journal-article","created":{"date-parts":[[2003,3,5]],"date-time":"2003-03-05T20:59:16Z","timestamp":1046897956000},"page":"1701-1712","source":"Crossref","is-referenced-by-count":56,"title":["An I47L substitution in the HOXD13 homeodomain causes a novel human limb malformation by producing a selective loss of function"],"prefix":"10.1242","volume":"130","author":[{"given":"Giuliana","family":"Caronia","sequence":"first","affiliation":[{"name":"Department of Molecular Biology and Functional Genomics, DIBIT-H San Raffaele,Via Olgettina 58, 20132 Milano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frances R.","family":"Goodman","sequence":"additional","affiliation":[{"name":"Molecular Medicine Unit, Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carole M. E.","family":"McKeown","sequence":"additional","affiliation":[{"name":"Clinical Genetics Unit, Birmingham Women's Hospital, Edgbaston, Birmingham B15 2TG, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter J.","family":"Scambler","sequence":"additional","affiliation":[{"name":"Molecular Medicine Unit, Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vincenzo","family":"Zappavigna","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Functional Genomics, DIBIT-H San Raffaele,Via Olgettina 58, 20132 Milano, Italy"},{"name":"Department of Animal Biology, University of Modena and Reggio Emilia, Via Campi 213\/d, Modena 41100, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"237","reference":[{"key":"2021042512455323900_REF1","doi-asserted-by":"crossref","unstructured":"Ades, S. E. and Sauer, R. T. (1995). 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