Identification of a novel<i>DLX5</i>mutation in a family with autosomal recessive split hand and foot malformation

Shamseldin, Hanan E.; Faden, Maha; Alashram, Walid; Alkuraya, Fowzan S.

doi:10.1136/jmedgenet-2011-100556

Cited by 77 publications

(86 citation statements)

References 41 publications

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“…Interestingly, a de novo 719 Mb duplication including DLX5/6 was recently described in an infant with SHFM, overgrowth of one great toe, microcephaly, and reduced height, suggesting that any alteration in the dosage of these genes may in fact be sufficient to cause SHFM [Velinov et al, 2012]. The redundancy of the DLX genes in this region suggests that heterozygous deletion or misregulation of both genes may be necessary for the human SHFM phenotype, unless there is a homozygous mutation in one of these genes, as demonstrated in one family to date [Shamseldin et al, 2012].…”

Section: Balanced/unbalanced Chromosome Rearrangementsmentioning

confidence: 85%

“…Single Gene Mutations SHFM1-DLX5. A homozygous mutation in DLX5 at the SHFM1 locus, which is otherwise associated with balanced and unbalanced chromosome rearrangements, has been identified in one family [Shamseldin et al, 2012] (see SHFM1 below).…”

Section: Molecular Basis At Specific Locimentioning

confidence: 99%

“…While these genes are expressed in developing vertebrate limbs, none is directly interrupted by any of the known rearrangement breakpoints. Moreover, mutations in these genes have not been identified in patients with SHFM, except for a homozygous missense mutation in the DLX5 homeodomain identified by autozygome/exome analysis in a consanguineous family with a complex SHFM phenotype that included tibial deficiency, dorsalization of the palms with cylindrical fingernails, craniofacial dysmorphism, and hearing loss [Shamseldin et al, 2012].…”

Section: Balanced/unbalanced Chromosome Rearrangementsmentioning

confidence: 99%

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Clinical, genetic, and molecular aspects of split‐hand/foot malformation: An update

Gurrieri

Everman

2013

American J of Med Genetics Pt A

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We here provide an update on the clinical, genetic, and molecular aspects of split-hand/foot malformation (SHFM). This rare condition, affecting 1 in 8,500-25,000 newborns, is extremely complex because of its variability in clinical presentation, irregularities in its inheritance pattern, and the heterogeneity of molecular genetic alterations that can be found in affected individuals. Both syndromal and nonsyndromal forms are reviewed and the major molecular genetic alterations thus far reported in association with SHFM are discussed. This updated overview should be helpful for clinicians in their efforts to make an appropriate clinical and genetic diagnosis, provide an accurate recurrence risk assessment, and formulate a management plan.

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Section: Balanced/unbalanced Chromosome Rearrangementsmentioning

confidence: 85%

Section: Molecular Basis At Specific Locimentioning

confidence: 99%

Section: Balanced/unbalanced Chromosome Rearrangementsmentioning

confidence: 99%

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Clinical, genetic, and molecular aspects of split‐hand/foot malformation: An update

Gurrieri

Everman

2013

American J of Med Genetics Pt A

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“…Intragenic homozygous mutation of WNT10b (MIM 601906), identified by linkage analysis and positional cloning in 2008, produces the autosomal-recessive SHFM6 phenotype. 13 While most SHFM1 cases are caused by various chromosomal aberrations such as deletions, inversions, translocations and duplications in a 1.5-Mb key interval on 7q21 encompassing the DLX5 and DLX6 genes, [19][20][21] SHFM1 in one family was reported to be due to a homozygous mutation of distal-less homeobox 5 (DLX5) (MIM 600028), 22 thus following autosomal-recessive inheritance. The limb malformation is also associated with hearing loss in the family.…”

Section: Introductionmentioning

confidence: 99%

Exome sequencing reveals a heterozygous DLX5 mutation in a Chinese family with autosomal-dominant split-hand/foot malformation

et al. 2014

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Split-hand/foot malformation (SHFM) is a congenital limb deformity due to the absence or dysplasia of central rays of the autopod. Six SHFM loci have already been identified. Here we describe a Chinese family with autosomal-dominant SHFM1 that has previously been mapped to 7q21.2-21.3. The two affected family members, mother and son, showed deep median clefts between toes, ectrodactyly and syndactyly; the mother also showed triphalangeal thumbs. Exome sequencing and variant screening of candidate genes in the six loci known to be responsible for SHFM revealed a novel heterozygous mutation, c.558G4T (p. (Gln186His)), in distal-less homeobox 5 (DLX5). As DLX5 encodes a transcription factor capable of transactivating MYC, we also tested whether the mutation could affect DLX5 transcription acitivity. Results from luciferase reporter assay revealed that a mutation in DLX5 compromised its transcriptional activity. This is the first report of a mutation in DLX5 leading to autosomal-dominant SHFM1.

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“…[1][2][3] DLX proteins are important regulators of developmental and differentiation processes, including skeletal development. [4][5][6] A missense mutation in DLX5 leads to split hand and foot malformation 7 and DLX5 and DLX6 are positive transcriptional regulators of osteochondroblastic differentiation. 6 DLX3 is defined as an osteogenic regulator, as human mutations in DLX3 lead to tricho-dento-osseous (TDO) syndrome, an ectodermal dysplasia that causes increased bone mineral density (BMD) in intramembranous and endochondral bones.…”

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confidence: 99%

DLX3 regulates bone mass by targeting genes supporting osteoblast differentiation and mineral homeostasis in vivo

Isaac

Gordon

et al. 2014

Cell Death Differ

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Human mutations and in vitro studies indicate that DLX3 has a crucial function in bone development, however, the in vivo role of DLX3 in endochondral ossification has not been established. Here, we identify DLX3 as a central attenuator of adult bone mass in the appendicular skeleton. Dynamic bone formation, histologic and micro-computed tomography analyses demonstrate that in vivo DLX3 conditional loss of function in mesenchymal cells (Prx1-Cre) and osteoblasts (OCN-Cre) results in increased bone mass accrual observed as early as 2 weeks that remains elevated throughout the lifespan owing to increased osteoblast activity and increased expression of bone matrix genes. Dlx3OCN-conditional knockout mice have more trabeculae that extend deeper in the medullary cavity and thicker cortical bone with an increased mineral apposition rate, decreased bone mineral density and increased cortical porosity. Trabecular TRAP staining and site-specific Q-PCR demonstrated that osteoclastic resorption remained normal on trabecular bone, whereas cortical bone exhibited altered osteoclast patterning on the periosteal surface associated with high Opg/Rankl ratios. Using RNA sequencing and chromatin immunoprecipitation-Seq analyses, we demonstrate that DLX3 regulates transcription factors crucial for bone formation such as Dlx5, Dlx6, Runx2 and Sp7 as well as genes important to mineral deposition (Ibsp, Enpp1, Mepe) and bone turnover (Opg). Furthermore, with the removal of DLX3, we observe increased occupancy of DLX5, as well as increased and earlier occupancy of RUNX2 on the bone-specific osteocalcin promoter. Together, these findings provide novel insight into mechanisms by which DLX3 attenuates bone mass accrual to support bone homeostasis by osteogenic gene pathway regulation. Endochondral bone formation (EBF) and homeostasis require a regulated program of mesenchymal condensation, chondrocyte differentiation, vascular invasion, cartilage resorption, osteoprogenitor recruitment and differentiation and bone remodeling. These key processes are under the control of essential bone transcription factors (TFs), including RUNX2, SP7 and homeodomain protein families such as HOX, MSX and DLX.1-3 DLX proteins are important regulators of developmental and differentiation processes, including skeletal development. [4][5][6] A missense mutation in DLX5 leads to split hand and foot malformation 7 and DLX5 and DLX6 are positive transcriptional regulators of osteochondroblastic differentiation. 6 DLX3 is defined as an osteogenic regulator, as human mutations in DLX3 lead to tricho-dento-osseous (TDO) syndrome, an ectodermal dysplasia that causes increased bone mineral density (BMD) in intramembranous and endochondral bones. In vitro, osteocalcin (Ocn), Runx2 9,10 and osteoactivin [9][10][11] are directly regulated by DLX3, and overexpression of DLX3 in osteoprogenitors stimulates transcription of osteogenic markers. 9Recently, we investigated the effects of neural crest deletion of Dlx3 in craniofacial bones. 12 The gene signature of craniofacial...

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Identification of a novelDLX5mutation in a family with autosomal recessive split hand and foot malformation

Abstract: This study identified the first intragenic DLX5 mutation in SHFM and raises interesting possibilities about a dual role for DLX5 in limb development.

Cited by 77 publications

References 41 publications

Clinical, genetic, and molecular aspects of split‐hand/foot malformation: An update

Clinical, genetic, and molecular aspects of split‐hand/foot malformation: An update

Exome sequencing reveals a heterozygous DLX5 mutation in a Chinese family with autosomal-dominant split-hand/foot malformation

DLX3 regulates bone mass by targeting genes supporting osteoblast differentiation and mineral homeostasis in vivo

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