Mendelian Inheritance in Man

Chondrodysplasia Grebe type (CGT) is an autosomal recessive disorder characterized by severe limb shortening and dysmorphogenesis. We have identified a causative point mutation in the gene encoding the bone morphogenetic protein (BMP)–like molecule, cartilage-derived morphogenetic protein–1 (CDMP-1). The mutation substitutes a tyrosine for the first of seven highly conserved cysteine residues in the mature active domain of the protein. We demonstrate that the mutation results in a protein that is not secreted and is inactive in vitro. It produces a dominant negative effect by preventing the secretion of other, related BMP family members. We present evidence that this may occur through the formation of heterodimers. The mutation and its proposed mechanism of action provide the first human genetic indication that composite expression patterns of different BMPs dictate limb and digit morphogenesis.

Disruption of human limb morphogenesis by a dominant negative mutation in CDMP1

Brachydactyly type A-1 (BDA-1; MIM 112500) is characterized by shortening or missing of the middle phalanges (Fig. 1a). It was first identified by Farabee in 1903 (ref. 2), is the first recorded example of a human anomaly with Mendelian autosomal-dominant inheritance and, as such, is cited in most genetic and biological textbooks. Here we show that mutations in IHH, which encodes Indian hedgehog, cause BDA-1. We have identified three heterozygous missense mutations in the region encoding the amino-terminal signaling domain in all affected members of three large, unrelated families. The three mutant amino acids, which are conserved across all vertebrates and invertebrates studied so far, are predicted to be adjacent on the surface of IHH.

Mutations in IHH, encoding Indian hedgehog, cause brachydactyly type A-1.

Inherited limb malformations provide a valuable resource for the identification of genes involved in limb development1,2. Brachydactyly type B (BDB), an autosomal dominant disorder, is the most severe of the brachydactylies3 and characterized by terminal deficiency of the fingers and toes. In the typical form of BDB, the thumbs and big toes are spared, sometimes with broadening or partial duplication4,5,6,7,8. The BDB1 locus was previously mapped to chromosome 9q22 within an interval of 7.5 cM (refs 9,10). Here we describe mutations in ROR2, which encodes the orphan receptor tyrosine kinase ROR2 (ref. 11), in three unrelated families with BDB1. We identified distinct heterozygous mutations (2 nonsense, 1 frameshift) within a 7–amino-acid segment of the 943–amino-acid protein, all of which predict truncation of the intracellular portion of the protein immediately after the tyrosine kinase domain. The localized nature of these mutations suggests that they confer a specific gain of function. We obtained further evidence for this by demonstrating that two patients heterozygous for 9q22 deletions including ROR2 do not exhibit BDB. Expression of the mouse orthologue, Ror2, early in limb development indicates that BDB arises as a primary defect of skeletal patterning.

Dominant mutations in ROR2, encoding an orphan receptor tyrosine kinase, cause brachydactyly type B.

The transforming growth factor β (TGF-β) family of signaling molecules, which includes TGF-βs, activins, inhibins, and numerous bone morphogenetic proteins (BMPs) and growth and differentiation factors (GDFs), has important functions in all cells and tissues, including soft connective tissues and the skeleton. Specific TGF-β family members play different roles in these tissues, and their activities are often balanced with those of other TGF-β family members and by interactions with other signaling pathways. Perturbations in TGF-β family pathways are associated with numerous human diseases with prominent involvement of the skeletal and cardiovascular systems. This review focuses on the role of this family of signaling molecules in the pathologies of connective tissues that manifest in rare genetic syndromes (e.g., syndromic presentations of thoracic aortic aneurysm), as well as in more common disorders (e.g., osteoarthritis and osteoporosis). Many of these diseases are caused by or result in pathological alterations of the complex relationship between the TGF-β family of signaling mediators and the extracellular matrix in connective tissues.

/pdf/tgf-b-family-signaling-in-connective-tissue-and-skeletal-ogeia0m9db.pdf

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

A search for patterns of malformation in the brachydactylies has resulted in new ways to identify the different types. Type A-1 can be characterised by a proportionate reduction of the middle phalanges. Type B is thought to be an amputation-like defect. In type C the fourth middle phalanx is usually the longest, and type E (Riccardi and Holmes, 1974) is characterised by short metacarpals and short distal phalanges. Short stature is usually present in type A-1 and type E brachydactyly (Riccardi and Holmes, 1974) and it may be present in some individuals with brachydactyly C. As short children have short hands, it is possible that in patients with very mild expressions of brachydactyly the cause of the short stature may be overlooked. It is suggested that in every child with proportionate short stature the hands should be carefully examined. If the hands are disproportionately short, if any distal creases are missing, if there is a shortening, however mild, of any finger, if any metacarpals are short, then it is important to have ϰ-rays to look for brachydactyly A-1, C, or E.

Much information is still needed. It is important in future reports to have skeletal surveys, pattern profile analyses, and to note the height of children with brachydactyly C. Most interesting of all will be when fetal limbs of each type become available for study.

https://jmg.bmj.com/content/jmedgenet/16/1/36.full.pdf

Naomi Fitch

Papers

Classification and identification of inherited brachydactylies