Mutation in the cartilage‐derived morphogenetic protein‐1 (CDMP1) gene in a kindred affected with fibular hypoplasia and complex brachydactyly (DuPan syndrome)

Faiyaz-Ul-Haque, Muhammad; Ahmad, Wasim; Zaidi, Syed Hassan Ejaz; Haque, Sayedul; Teebi, Ahmad S.; Siddique, M.; Cohn, Daniel H.; Lc, Tsui

doi:10.1034/j.1399-0004.2002.610610.x

Cited by 81 publications

(56 citation statements)

References 19 publications

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“…A mutation in the cartilage-derived morphogenetic protein-1 (CDMP-1) gene has been identified in a large family with variable hand and foot abnormalities, including a child with isolated vertical talus. Mutations in CDMP-1 have been previously described in Grebe and Hunter-Thompson forms of acromelic skeletal dysplasia as well as in DuPan syndrome [26][27][28]; these disorders present with severe limb abnormalities. Mutations in CDMP-1 have also been described in patients with brachydactyly type C, a condition that is characterized by short middle phalanges and first metacarpals [29].…”

Section: Geneticsmentioning

confidence: 98%

A new approach to the treatment of congenital vertical talus

Alaee

Boehm

Dobbs

2007

Journal of Children's Orthopaedics

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Congenital vertical talus is an uncommon foot deformity that is present at birth and results in a rigid flatfoot deformity. Left untreated the deformity can result in pain and disability. Though the exact etiology of vertical talus is unknown, an increasing number of cases have been shown to have a genetic cause. Approximately 50% of all cases of vertical talus are associated with other neuromuscular abnormalities or known genetic syndromes. The remaining 50% of cases were once thought to be idiopathic in nature. However, there is increasing evidence that many of these cases are related to single gene defects. Most patients with vertical talus have been treated with major reconstructive surgeries that are fraught with complications such as wound necrosis, talar necrosis, undercorrection of the deformity, stiffness of the ankle and subtalar joint, and the eventual need for multiple operative procedures. Recently, a new approach to vertical talus that consists of serial casting and minimal surgery has resulted in excellent correction in the short-term. Longer follow-up will be necessary to ensure maintenance of correction with this new technique. A less invasive approach to the correction of vertical talus may provide more favorable long-term outcomes than more extensive surgery as has been shown to be true for clubfoot outcomes.

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Section: Geneticsmentioning

confidence: 98%

A new approach to the treatment of congenital vertical talus

Alaee

Boehm

Dobbs

2007

Journal of Children's Orthopaedics

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“…Mutations in the prodomain of GDF5 cause a recessive form of BDC, presumably by means of a gene dosage effect . GDF5 is pivotal for chondrogenesis in humans, because homozygous loss of function mutations in GDF5 cause recessive generalized acromesomelic chondrodysplasia of the Grebe (MIM#200700), Hunter-Thomson (MIM#201250), and Du Pan (MIM#228900) type (Thomas et al, 1996Faiyaz-Ul-Haque et al, 2002). Furthermore, recessive homozygous mutations in the high affinity receptor BMPR1B also cause a severe form of acromesomelic chondrodysplasia with brachydactyly (Demirhan et al, 2005).…”

Section: Condensation Of the Digit Anlagenmentioning

confidence: 99%

Mechanisms of digit formation: Human malformation syndromes tell the story

Stricker

Mundlos

2011

Developmental Dynamics

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Identifying the genetic basis of human limb malformation disorders has been instrumental in improving our understanding of limb development. Abnormalities of the hands and/or feet include defects affecting patterning, establishment, elongation, and segmentation of cartilaginous condensations, as well as growth of the individual skeletal elements. While the phenotype of such malformations is highly diverse, the mutations identified to date cluster in genes implicated in a limited number of molecular pathways, namely hedgehog, Wnt, and bone morphogenetic protein. The latter pathway appears to function as a key molecular network regulating different phases of digit and joint development. Studies in animal models not only extended our insight into the pathogenesis of these conditions, but have also contributed to our understanding of the in vivo functions and interactions of these key players. This review is aimed at integrating the current understanding of human digit malformations into the increasing knowledge of the molecular mechanisms of digit development. Developmental Dynamics 240:990-1004,

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“…3 All reported mutations in GDF5 associated with ACD are caused by a homozygous functional loss of GDF5, which is caused by either deletions, duplications, or insertions leading to a premature translational stop or caused by point mutations targeting the cleavage site or the mature domain of GDF5, thereby compromising its regular function. [4][5][6][7][8][9][10][11][12][13] Interestingly, one individual with a homozygous mutation in BMPR1B has been reported presenting with a subtype of ACD with additional genital anomalies, 14 implicating that mutations in the ligand and its receptor can cause similar phenotypes. Heterozygous carriers of dominant-negative mutations in BMPR1B are usually affected by brachydactyly-type A2 (BDA2; MIM number 112600), which is characterized by a shortened middle phalanx of the index finger and variable clinodactyly of the fifth finger.…”

Section: Introductionmentioning

confidence: 99%

Homozygous missense and nonsense mutations in BMPR1B cause acromesomelic chondrodysplasia-type Grebe

et al. 2013

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Acromesomelic chondrodysplasias (ACDs) are characterized by disproportionate shortening of the appendicular skeleton, predominantly affecting the middle (forearms and forelegs) and distal segments (hands and feet). Here, we present two consanguineous families with missense (c.157T4C, p.(C53R)) or nonsense (c.657G4A, p.(W219*)) mutations in BMPR1B. Homozygous affected individuals show clinical and radiographic findings consistent with ACD-type Grebe. Functional analysis of the missense mutation C53R revealed that the mutated receptor was partially located at the cell membrane. In contrast to the wild-type receptor, C53R mutation hindered the activation of the receptor by its ligand GDF5, as shown by reporter gene assay. Further, overexpression of the C53R mutation in an in vitro chondrogenesis assay showed no effect on cell differentiation, indicating a loss of function. The nonsense mutation (c.657G4A, p.(W219*)) introduces a premature stop codon, which is predicted to be subject to nonsense-mediated mRNA decay, causing reduced protein translation of the mutant allele. A lossof-function effect of both mutations causing recessive ACD-type Grebe is further supported by the mild brachydactyly or even non-penetrance of these mutations observed in the heterozygous parents. In contrast, dominant-negative BMPR1B mutations described previously are associated with autosomal-dominant brachydactyly-type A2.

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Mutation in the cartilage‐derived morphogenetic protein‐1 (CDMP1) gene in a kindred affected with fibular hypoplasia and complex brachydactyly (DuPan syndrome)

Cited by 81 publications

References 19 publications

A new approach to the treatment of congenital vertical talus

A new approach to the treatment of congenital vertical talus

Mechanisms of digit formation: Human malformation syndromes tell the story

Homozygous missense and nonsense mutations in BMPR1B cause acromesomelic chondrodysplasia-type Grebe

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