Distinct Mutations in the Receptor Tyrosine Kinase Gene ROR2 Cause Brachydactyly Type B Georg C. Schwabe, Sigrid Tinschert, Christian Buschow, Peter.

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Distinct Mutations in the Receptor Tyrosine Kinase Gene ROR2 Cause Brachydactyly Type B Georg C. Schwabe, Sigrid Tinschert, Christian Buschow, Peter Meinecke, Gerhard Wolff, Gabriele Gillessen-Kaesbach, Michael Oldridge, Andrew O.M. Wilkie, Reyhan Kömec, Stefan Mundlos The American Journal of Human Genetics Volume 67, Issue 4, Pages 822-831 (October 2000) DOI: 10.1086/303084 Copyright © 2000 The American Society of Human Genetics Terms and Conditions

Figure 1 Pedigrees of families 1–5 with BDB. The homozygous individual is indicated by an arrow. The American Journal of Human Genetics 2000 67, 822-831DOI: (10.1086/303084) Copyright © 2000 The American Society of Human Genetics Terms and Conditions

Figure 2 Left, Parents with BDB and their affected child, from family 1. Molecular analysis in this family revealed a 5-bp deletion in exon 8 of ROR2, with individual IV/1 being homozygously affected. Note the characteristic phenotype in the parents (A), with distal hypoplasia of phalanges 2, 4, and 5, nail dysplasia, and distal symphalangism. Their son shows a severe reduction deformity of all limbs. B, Presentation at birth. Corresponding pictures of the right hand (C) and foot (D) demonstrate almost complete absence of phalanges and nails. Also shown are the right hand after several orthopedic hand operations (E) and of the foot (F), as well as total-body view (G) of same patient at age 7.5 years. Note brachymelia of arms. Right, Radiological features of homozygously affected individual. A, Humerus, radius, ulna, and hand, after birth. Note normal structure but shortness of long bones and absence/hypoplasia of phalanges and metacarpals. B, Right hand at age 6 mo. C, Hands at age 2.5 years. D, Feet at age 2.5 years. Note complete disorganization and partial fusion of metacarpals, as well as shortening and cubic deformation of metatarsals. E, Anterior-posterior radiograph of thoracic and lumbar spine at age 7.5 years. Note the presence of multiple vertebral malformations, between T6 and T12 (arrowheads) and at L5/6, and hypoplasia of the sacrum (arrow). The American Journal of Human Genetics 2000 67, 822-831DOI: (10.1086/303084) Copyright © 2000 The American Society of Human Genetics Terms and Conditions

Figure 3 ROR2 mutations in families with BDB. A, wt sequences are shown in the top line of each set; the mutated sequence is in boldface, exon sequences are in capital letters, and intron sequences are in lowercase. The predicted amino acid sequence of the mutated allele is shown in the bottom line of each set, with the altered sequence in italics. The mutation in family 1 is a 5-bp deletion (1321–1325del5) in exon 8, resulting in a frameshift and in a stop codon after 14 amino acids. Family 2 has an alteration in intron 8, which deletes 3 bp (CTC) and inserts 19 bp (IVS8+3 → +5del3ins19) at the 5′ splice site. This changes the wt splice site and results in the generation of an aberrant splice product using a new splice-donor site with a perfect consensus sequence (boxed). Families 3 and 4 have a 1-bp insertion (1398–1399insA) at the 5′ end of exon 9, resulting in a frameshift and in a premature termination codon after 57 amino acids. A 2278C→T missense mutation was detected in family 5, resulting in a stop codon at position Q760X. B, Gel analysis of PCR-amplified mutant region in families 1, 2, and 4. The 5-bp frameshift mutation in family 1 deletes a site for MwoI, which cuts the wt sequence into two fragments. The unaffected family member (left lane) shows complete digestion, the heterozygous members show partial digestion, and the homozygous patient (arrow) shows no digestion. The RT-PCR product from a heterozygous family member containing the mutated region resulting in a 334-bp fragment was digested with MwoI (lane 3) and was compared with controls (lanes 1 and 2). The undigested fragment (arrow), which corresponds to the mutated allele, is of an intensity approximately equal to that of the two digested wt fragments together (223 and 111 bp, arrowheads). The controls show complete digestion. The splice-site mutation in family 2 removes a BsaI restriction site. The wt allele is cut into two fragments, of 271 and 113 bp, whereas the mutant allele remains undigested (arrow). The affected son in family 5 has a C→T transition at codon 2278. This nucleotide change creates a new restriction site for AccI, which cuts the PCR-amplified sequence into two fragments of similar size (arrow). Amplified DNA from unaffected parents is not cut. Molecular-size markers are shown on the left. The American Journal of Human Genetics 2000 67, 822-831DOI: (10.1086/303084) Copyright © 2000 The American Society of Human Genetics Terms and Conditions

Figure 4 ROR2-protein domains and model for predicted consequences of ROR2, mutations. A, Normal structure of ROR2, showing immunoglobulin-like, cysteine-rich, kringle, transmembrane, TK (active center white circle), serine-threonine–rich, and proline-rich domains. The mutations causing BDB are shown on the left; mutations causing Robinow syndrome are on the right. The mutations reported in this article are in boldface; all others have been published elsewhere (Afzal et al. 2000; Oldridge et al. 2000; van Bokhoven et al. 2000). B, Schematic of the BDB mutations located distal (left), as in family 5, and proximal (right) to the TK domain, as described for families 1–4. Truncation of the intracellular serine-threonine–rich and proline-rich domains, as well as truncation of the entire intracellular portion of ROR2, results in dominant BDB. C, In contrast (left to right), extracellular truncation of ROR2, truncation within the TK domain, or selective inactivation of TK activity, which lead to autosomal recessive Robinow syndrome. The American Journal of Human Genetics 2000 67, 822-831DOI: (10.1086/303084) Copyright © 2000 The American Society of Human Genetics Terms and Conditions

Figure 5 Left, Phenotypic spectrum of BDB mutations located proximal to the TK domain (family 1A and B and family 3 C–F), demonstrating the different degrees of severity (designated grades 1–4, as described in the Results section). The severe phenotype (grade 4) is shown in A. Note complete absence of distal phalanges and nails in fingers 2–5. The moderately severe phenotype (grade 3), characterized by absence of nails and/or terminal phalanges in three fingers, is present in the left hand and is shown in B, whereas the right hand of this patient exhibits the severe phenotype. The intermediate type (grade 2) is shown in C and D.C, Absence of distal phalanges of finger 4 and hypoplasia of distal phalanges of fingers 2, 3, and 5, in a child (III/4). D, Individual II/3, with bilateral shortening of distal phalanges and hypoplasia/absence of nails, primarily of 4th finger. E, Individual I/1, with the mild phenotype (grade 1), showing moderate hypoplasia of distal phalanges, normal nails, but distal symphalangism of fingers 2–5 and camptodactyly of finger 5. F, Individual II/6, showing the intermediate phenotype, with absence of the distal phalanx of digit 4 of the right hand (grade 2), bilateral distal symphalangism of fingers 2–5, short fingers, but normal nails on the left hand (grade 1). Right, Radiographs of individuals of family 3. A, Bilateral hypoplasia of distal phalanges 2, 3, and 5, and absence of distal phalanx 4 of individual III/4 (also shown in Left, C). The metacarpal bones, proximal phalanges, and thumbs are shaped regularly. B, Individual III/2, with loss of distal phalanges of fingers 2 and 4 and distal symphalangism of finger 3 and finger 5 of the left hand. C, Magnification of radiograph showing distal part of fingers of individual II/3 (also shown in Left, E). Note distal symphalangism (open arrow) with “fusion” of distal and middle phalanges of fingers 2–4. In comparison, the joint between proximal phalanges and metacarpals has developed normally (arrow). D, Magnification of carpal bones of individual II/6 (also shown in Left, F). Note fusion of hamate with capitate (asterisk), (note line of fusion [arrow]) and trapezium with trapezoid of carpus. The American Journal of Human Genetics 2000 67, 822-831DOI: (10.1086/303084) Copyright © 2000 The American Society of Human Genetics Terms and Conditions