Topic
Synpolydactyly
About: Synpolydactyly is a research topic. Over the lifetime, 122 publications have been published within this topic receiving 5344 citations. The topic is also known as: syndactyly type 2 & Synpolydactyly.
Papers published on a yearly basis
Papers
TL;DR: It is reported here that targeted disruption of the Hoxa-13 gene leads to a specific forelimb and hindlimb autopodal phenotype, distinct from that of theHoxd-13 paralogous gene inactivation, indicating that these genes act in a partially redundant manner.
Abstract: Members of the Abdominal-B-related Hox gene subfamily (belonging to homology groups 9 to 13) are coordinately expressed during limb bud development. Only two genes from homology group 13 (Hoxa-13 and Hoxd-13) are specifically expressed in the developing distal region (the autopod), which displays the most complex and evolutionarily flexible pattern among limb ‘segments’. We report here that targeted disruption of the Hoxa-13 gene leads to a specific forelimb and hindlimb autopodal phenotype, distinct from that of the Hoxd-13 paralogous gene inactivation. In both limbs, Hoxa-13 loss of function results in the lack of formation of the most anterior digit and to altered morphogenesis of some ‘preaxial’ carpal/tarsal elements. We have generated mice with all possible combinations of disrupted Hoxa-13 and/or Hoxd-13 alleles, which allowed us to investigate the degree of functional specificity versus redundancy of the corresponding gene products in the developing limb autopod. The phenotype of any double mutant was much more severe than the sum of the phenotypes seen in the corresponding single mutants, indicating that these genes act in a partially redundant manner. Our major findings were: (1) an abnormal autopodal phenotype in Hoxa-13+/−/Hoxd-13+/− double heterozygous mutants, which mostly consists of subsets of the alterations seen in each individual homozygous mutant, and therefore appears to result from quantitative, rather than qualitative, homeoprotein deficiency; (2) partly distinct alterations in mutants harboring a single non-disrupted allele of Hoxa-13 or Hoxd-13, indicating that the remaining reduced protein amounts are not functionally equivalent; (3) a polydactyly in the forelimbs of Hoxa-13+/−/Hoxd-13−/−double mutants, consisting of seven symmetrically arranged, truncated and mostly non-segmented digits; (4) an almost complete lack of chondrified condensations in the autopods of double homozygous mutants, showing that the activity of group 13 Hox gene products is essential for autopodal patterning in tetrapod limbs.
470 citations
TL;DR: Observations suggest an important role for Hox genes in controlling localized growth of those cells that contribute to forming the appendicular skeleton in mice with a disruption in the homeobox-containing gene hoxd-11.
Abstract: Using gene targeting, we have created mice with a disruption in the homeobox-containing gene hoxd-11. Homozygous mutants are viable and the only outwardly apparent abnormality is male infertility. Skeletons of mutant mice show a homeotic transformation that repatterns the sacrum such that each vertebra adopts the structure of the next most anterior vertebra. Defects are also seen in the bones of the limb, including regional malformations at the distal end of the forelimb affecting the length and structure of phalanges and metacarpals, inappropriate fusions between wrist bones, and defects at the most distal end in the long bones of the radius and ulna. The phenotypes show both incomplete penetrance and variable expressivity. In contrast to the defects observed in the vertebral column, the phenotypes in the appendicular skeleton do not resemble homeotic transformations, but rather regional malformations in the shapes, length and segmentation of bones. Our results are discussed in the context of two other recent gene targeting studies involving the paralogous gene hoxa-11 and another member of the Hox D locus, hoxd-13. The position of these limb deformities reflects the temporal and structural colinearity of the Hox genes, such that inactivation of 3′ genes has a more proximal phenotypic boundary (affecting both the zeugopod and autopod of the limb) than that of the more 5′ genes (affecting only the autopod). Taken together, these observations suggest an important role for Hox genes in controlling localized growth of those cells that contribute to forming the appendicular skeleton.
293 citations
TL;DR: A variety of limb malformations now known to be caused by specific different mutations in these two genes are described, including polyalanine tract expansions, nonsense mutations, and missense mutations, many with phenotypic consequences that could not have been predicted from previous knowledge of mouse models or HOX protein function.
Abstract: HOX genes encode a family of transcription factors of fundamental importance for body patterning during embryonic development. Humans, like most vertebrates, have 39 HOX genes organized into four clusters, with major roles in the development of the central nervous system, axial skeleton, gastrointestinal and urogenital tracts, external genitalia, and limbs. The first two limb malformations shown to be caused by mutations in the human HOX genes were synpolydactyly and hand-foot-genital syndrome, which result from mutations in HOXD13 and HOXA13, respectively. This review describes a variety of limb malformations now known to be caused by specific different mutations in these two genes, including polyalanine tract expansions, nonsense mutations, and missense mutations, many with phenotypic consequences that could not have been predicted from previous knowledge of mouse models or HOX protein function. Limb malformations may also result from chromosomal deletions involving the HOXD and HOXA clusters, and from regulatory mutations affecting single or multiple HOX genes.
232 citations
TL;DR: The remarkable correlation between phenotype and expansion size suggests that expansion of the tract leads to a specific gain of function in the mutant HOXD13 protein, and has interesting implications for the role of polyalanine tracts in the control of transcription.
Abstract: Synpolydactyly (SPD) is a dominantly inherited congenital limb malformation. Typical cases have 3/4 finger and 4/5 toe syndactyly, with a duplicated digit in the syndactylous web, but incomplete penetrance and variable expressivity are common. The condition has recently been shown to be caused by expansions of an imperfect trinucleotide repeat sequence encoding a 15-residue polyalanine tract in HOXD13. We have studied 16 new and 4 previously published SPD families, with between 7 and 14 extra residues in the tract, to analyze the molecular basis for the observed variation in phenotype. Although there is no evidence of change in expansion size within families, even over six generations, there is a highly significant increase in the penetrance and severity of phenotype with increasing expansion size, affecting both hands (P = 0.012) and feet (P < 0.00005). Affected individuals from a family with a 14-alanine expansion, the largest so far reported, all have a strikingly similar and unusually severe limb phenotype, involving the first digits and distal carpals. Affected males from this family also have hypospadias, not previously described in SPD, but consistent with HOXD13 expression in the developing genital tubercle. The remarkable correlation between phenotype and expansion size suggests that expansion of the tract leads to a specific gain of function in the mutant HOXD13 protein, and has interesting implications for the role of polyalanine tracts in the control of transcription.
213 citations
TL;DR: A molecular classification of TF IDRs is presented, which provides a framework to dissect TF function in diseases associated with transcriptional dysregulation and suggests that unblending of transcriptional condensates may underlie human pathologies.
168 citations
Related Topics (5)
Performance Metrics
| Year | Papers |
|---|---|
| 2021 | 3 |
| 2020 | 3 |
| 2019 | 4 |
| 2018 | 4 |
| 2017 | 6 |
| 2016 | 5 |