Alternative titles; symbols
HGNC Approved Gene Symbol: ROR2
Cytogenetic location: 9q22.31 Genomic coordinates (GRCh38) : 9:91,722,601-91,950,228 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9q22.31 | Brachydactyly, type B1 | 113000 | Autosomal dominant | 3 |
| Robinow syndrome, autosomal recessive | 268310 | Autosomal recessive | 3 |
The receptor tyrosine kinases (RTK), including ROR1, are a large superfamily of transmembrane glycoproteins that function as cell surface receptors. RTKs play a role in the control of most basic cellular processes including cell proliferation, differentiation, migration and metabolism (summary by Afzal and Jeffery, 2003).
By degenerate PCR using primers based on conserved regions of NTRK1 (191315) and NTRK2 (600456), Masiakowski and Carroll (1992) identified 2 additional members of the TRK family, NTRKR1 (ROR1; 602336) and NTRKR2, also called ROR2. Masiakowski and Carroll (1992) showed that NTRKR2 encodes a predicted 943-amino acid protein with in vitro protein kinase activity.
Receptor tyrosine kinases often have critical roles in particular cell lineages by initiating signal cascades in those lineages. Many lineage-restricted receptor tyrosine kinases were initially identified as 'orphans' homologous to known receptors, and only subsequently used to identify their unknown growth factors. DeChiara et al. (2000) identified one such orphan, encoded by Ror2. They reported that disruption of mouse Ror2 leads to profound skeletal abnormalities, with essentially all endochondrally derived bones foreshortened or misshapen, albeit to differing degrees. Further, they found that Ror2 is selectively expressed in the chondrocytes of all developing cartilage anlagen, where it is essential during initial growth and patterning, as well as subsequently in the proliferating chondrocytes of mature growth plates, where it is required for normal expansion. Thus, Ror2 encodes a receptor-like tyrosine kinase that is selectively expressed in, and particularly important for, the chondrocyte lineage.
By radiation hybrid mapping between D9S1842 and D9S196 on 2 independent panels, Deloukas et al., 1998 mapped the ROR2 gene to chromosome 9q22. By FISH analysis, Oldridge et al., 2000 confirmed localization of the ROR2 gene to chromosome 9q22.
The mouse Ror2 gene maps to chromosome 13, in a region of conserved synteny with human chromosome 9q (Oishi et al., 1999).
Using mouse proteins, Mikels and Nusse (2006) demonstrated that Ror2 is a receptor for Wnt5a (164975) and serves to inhibit canonical Wnt signaling.
By immunostaining, Zhang et al. (2024) showed that ligand wnt5b (606361) and its plasma membrane-bound receptor ror2 were expressed and colocalized on cell protrusions in PAC2 zebrafish fibroblasts. Overexpression and knockout analyses in PAC2 cells revealed that wnt5b and ror2 formed a ligand-receptor complex and were transported from producing cells to receiving cells. During transport, wnt5b and the N-terminal part of ror2 faced the extracellular side of the membrane and were loaded together on signaling filopodia that the authors referred to as cytonemes, and the ligand-receptor complex was taken up by dynamin-dependent endocytosis into receiving cells via the cytonemes. The same transport was seen in zebrafish embryos, and further analysis with living zebrafish embryos indicated that ror2 bound to wnt5b with high affinity at the plasma membrane of producing cells, and that structural integrity of the complex was maintained during both transportation and subsequent uptake into receiving cells. Knockout and overexpression analyses in zebrafish revealed that wnt5b-ror2 regulated cytoneme formation, as binding between wnt5b and ror2 triggered the Wnt-planar cell polarity (PCP) signaling pathway, which induced long wnt5b-ror2-bearing cytonemes to facilitate spreading of wnt5b and ror2. The cytonemes were stabilized through irsp53 (BAIAP2; 605475) and Wnt-JNK (see 601158) signaling, and ror2 directly delivered by cytonemes was required for paracrine Wnt-JNK activation, indicating that the transferred wnt5b-ror2 complex maintained its activity in target cells. In addition to activating JNK signaling, paracrine ror2 also repressed beta-catenin (CTNNB1; 116806) signaling, thereby influencing convergence and extension in zebrafish development.
Brachydactyly, Type B1
Inherited limb malformations provide a valuable resource for identification of genes involved in limb development (Innis and Mortlock, 1998; Manouvrier-Hanu et al., 1999). Brachydactyly type B (BDB1; 113000), an autosomal dominant disorder, is the most severe of the brachydactylies and is 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 duplication. The BDB1 locus was mapped to 9q22 within an interval of 7.5 cM (Gong et al., 1999; Oldridge et al., 1999). Oldridge et al. (2000) identified distinct heterozygous mutations (2 nonsense, 1 frameshift) within a 7-amino acid segment of the 943-amino acid ROR2 protein, all of which predicted truncation of the intracellular portion of the protein immediately after the tyrosine kinase domain. The localized nature of these mutations suggested that they confer a specific gain of function. Oldridge et al. (2000) obtained further evidence for this by demonstrating that 2 patients heterozygous for 9q22 deletions including ROR2 did not exhibit BDB. Expression of the mouse ortholog, Ror2, early in limb development indicated that BDB arises as a primary defect of skeletal patterning.
In 5 families with BDB, Schwabe et al. (2000) found 4 novel mutations in ROR2: 2 frameshifts (see, e.g., 602337.0008), 1 splice mutation, and 1 nonsense mutation. The mutations predicted truncation of the protein within 2 distinct regions immediately before and after the tyrosine kinase (TK) domain, resulting in a complete or partial loss of the intracellular portion of the protein. Patients with the distal mutations had a more severe phenotype than did those with the proximal mutations.
Bacchelli et al. (2003) reviewed 4 affected members of a large Welsh family with a dominantly inherited form of isolated brachydactyly first described by Schott (1978), who designated it hereditary brachydactyly with nail dysplasia. Although Schott (1979) recognized that the external and radiologic appearance of the affected individuals' hands were very similar to brachydactyly type B1, he maintained that the disorder could be distinguished from BDB1 by the complete absence of foot involvement. Bacchelli et al. (2003) found, however, that in addition to hand anomalies typical of BDB, affected members of the Welsh kindred had subtle but definite foot involvement, including mild shortening of the second to fifth toes, occasional nail hypoplasia, and clinically evident distal symphalangism. Facial appearance was also typical of BDB, including a short philtrum and a prominent nose with a high bridge and bulbous tip. Direct sequencing of ROR2 demonstrated a nonsense mutation (W749X; 602337.0009). A heterozygous G-to-A transition in exon 9 (2247G-A) was responsible for the premature stop. The same nonsense change in codon 749 had been reported in a German family with typical BDB, although the underlying base change in that family was different (2246G-A).
In a large Turkish family with a mild BDB1 phenotype, known to be negative for mutation in the NOG (602991) and GDF5 (601146) genes, Kjaer et al. (2009) identified a heterozygous truncating mutation in the ROR2 gene (602337.0013).
Robinow Syndrome, Autosomal Recessive 1
autosomal recessive Robinow syndrome-1 (RRS1; 268310) is a severe skeletal dysplasia with generalized shortening of the bones of the limbs, segmental defects of the spine, brachydactyly, and a dysmorphic facial appearance. Afzal et al. (2000) mapped the gene mutant in this disorder to 9q22, a region that overlaps the locus for autosomal dominant brachydactyly type B. The identification of ROR2, encoding a receptor tyrosine kinase, as the gene mutated in brachydactyly type B and in the mesomelic dwarfing in mice homozygous for insertions in the Ror2 gene, made this gene a candidate for autosomal recessive Robinow syndrome. Afzal et al. (2000) reported homozygous missense mutations (e.g., 602337.0005) in both intracellular and extracellular domains of ROR2 in affected individuals from 3 unrelated consanguineous families, and a Q502X mutation (602337.0004) that removed the tyrosine kinase domain in all subsequent 3-prime regions of the gene in 14 patients from 7 families from Oman. The nature of these mutations suggested that this form of Robinow syndrome is caused by loss of ROR2 activity. Identification of mutations from 3 distinct domains (containing frizzled-like, kringle, and tyrosine kinase motifs) indicated that these are all essential for ROR2 function.
Van Bokhoven et al. (2000) also mapped autosomal recessive Robinow syndrome to chromosome 9q21-q22 and detected homozygous ROR2 mutations in a cohort of 10 families of Turkish descent and 1 of Pakistani descent.
Tufan et al. (2005) reported 2 patients with autosomal recessive Robinow syndrome and mutations in the ROR2 gene: one homozygous for a deletion (602337.0010) and the other compound heterozygous for a missense (R184C; 602337.0005) and a nonsense (R119X; 602337.0011) mutation.
By bioinformatic analysis and immunoprecipitation studies, Chen et al. (2005) showed that endoplasmic reticulum (ER) retention was the mechanism underlying Robinow syndrome-1. Specifically, mutant alleles of ROR2, including the R184C mutation, that are associated with autosomal recessive Robinow syndrome were retained within the ER, whereas wildtype and nonpathogenic alleles were exported to the plasma membrane.
In an unrelated boy and girl with autosomal recessive Robinow syndrome, Ali et al. (2007) identified homozygosity for different missense mutations, respectively, located in the proximal region of the extracellular frizzled-like domain of the ROR2 gene. In studies in HeLa cells, the authors demonstrated that the mutated proteins were retained in the ER and failed to reach the plasma membrane. Noting the clustering of Robinow-causing mutations in the extracellular frizzled-like cysteine-rich domain of ROR2, Ali et al. (2007) suggested that there is a stringent requirement for the correct folding of this domain prior to export of ROR2 from the ER.
In 2 sib pairs with Robinow syndrome from the same extended family, Brunetti-Pierri et al. (2008) identified homozygosity for a deletion encompassing exons 6 and 7 of the ROR2 gene (602337.0012); all 4 unaffected parents were heterozygous for the deletion.
Van Bokhoven and Brunner (2002) pointed out that the mechanism of divergent phenotypes of disorders caused by allelic mutations is illustrated by dominant BDB and recessive Robinow syndrome which are caused, respectively, by gain-of-function and loss-of-function mutations in the ROR2 gene.
Afzal and Jeffery (2003) presented a compilation of the defects in the ROR2 gene leading to autosomal recessive Robinow syndrome and autosomal dominant BDB and discussed possible genotype-phenotype correlations.
Recessive Robinow Syndrome with Severe Malformations of the Hands and Feet
In a large Turkish kindred in which many members over at least 6 generations had dominant BDB1, Schwabe et al. (2000) described a man, born of consanguineous parents with BDB1, who was homozygous for a 5-bp deletion proximal to the TK domain, resulting in frameshift at the arg441 residue (602337.0008). His phenotype resembled an extreme form of brachydactyly, with extensive aplasia/hypoplasia of the phalanges and metacarpals/metatarsals and absence of nails. In addition, he had vertebral anomalies, brachymelia anomalies (short arms), and a ventricular septal defect--features reminiscent of Robinow syndrome. The phenotype in this patient suggested a specific mutation effect that cannot be explained by simple haploinsufficiency and that is distinct from that in Robinow syndrome.
Schwarzer et al. (2009) reported an R441X mutation in the ROR2 gene (602337.0014) in an Omani patient exhibiting features of Robinow syndrome in conjunction with complex, symmetric brachy-syn-polydactyly of the hands and oligodactyly of the feet with absent toes 2 to 4. The Omani parents were healthy, had no features of Robinow syndrome or BDB1, and were distantly related by mothers of the same tribal background. The R441X mutation was located at the same position as the frameshift mutation at arg441. Transfection experiments with a series of mutant transcripts revealed that recessive Robinow syndrome (RRS) mutant proteins, such as Q502X and W720X (602337.0006), were less abundant and retained intracellularly, whereas BDB1 mutants, such as W749X, were stable and predominantly located at the cell membrane. Both the frameshift mutation and the R441X mutation showed an intermediate pattern with membrane localization but also high ER retention, although the R441X mutant had a significantly lower total protein level and less membrane-associated protein than the frameshift mutant. There was a correlation between the severity of BDB1, the location of the mutation, and the amount of membrane-associated ROR2. Membrane protein fraction quantification revealed a gradient of distribution and stability correlating with the clinical phenotypes. This gradual model was confirmed by crossing mouse models for RRS and BDB1, yielding double heterozygous animals that exhibited an intermediate phenotype. Schwarzer et al. (2009) proposed a model in which the phenotypic outcome of ROR2 mutations is determined by 2 threshold levels: the degree of protein retention/degradation determines the RRS phenotype, whereas the amount of mutant protein reaching the plasma membrane determines the severity of the BDB1 phenotype. A mixture of both effects can result in a balance of gain of function and loss of function and, consequently, an overlapping phenotype.
Takeuchi et al. (2000) generated mice with a mutation in the Ror2 gene and observed that homozygous mutant mice died just after birth, exhibiting dwarfism, severe cyanosis, and short limbs and tails. Whole-mount in situ hybridization analysis showed that Ror2 is expressed in the branchial arches, heart, and limb/tailbuds, in addition to the developing nervous system. The Ror2-deficient mice had cardiac septal defects and skeletal abnormalities, including shorter limbs, vertebrae, and facial structure, with a particular defect in their distal portions. Takeuchi et al. (2000) concluded that Ror2 plays essential roles in the development of the heart and in limb/tail formation, in particular cardiac septal formation and ossification of distal portions of limbs and tails.
Nomi et al. (2001) bred double-mutant mice lacking both the Ror1 and Ror2 genes. Using skeletal preparations, they observed that Ror1/Ror2 double-mutant mice showed skeletal abnormalities more severe than those seen in Ror2 mutant mice, including a sternal defect, dysplasia of the symphysis of the pubic bone. Histologic analysis of heart sections revealed that double-mutant mice exhibited complete transposition of the great arteries, an observation not seen in either single mutant. Nomi et al. (2001) concluded that Ror1 and Ror2 are functionally redundant and that they interact genetically in skeletal and cardiac development.
Oishi et al. (2003) found that both Ror2-null and Wnt5a (164975)-null mice showed dwarfism, facial abnormalities, short limbs and tails, dysplasia of lungs and genitals, and ventricular septal defects. In vitro binding assay revealed that Wnt5a binds to the Ror2 and activates the noncanonical Wnt pathway. The findings indicated that Wnt5a and Ror2 interact physically and functionally, and suggested that Ror2 acts as a receptor for Wnt5a to activate noncanonical Wnt signaling.
Schwabe et al. (2004) analyzed Ror2 -/- mice as a model for the developmental pathology of Robinow syndrome. They demonstrated that vertebral malformations in the mutant mice were due to reductions in the presomitic mesoderm and defects in somitogenesis. Mesomelic limb shortening in the mice was a consequence of perturbed chondrocyte differentiation. The craniofacial phenotype was caused by a midline outgrowth defect. Ror2 expression in the genital tubercle and its reduced size in Ror2 -/- mice suggested that Ror2 is involved in genital development. Schwabe et al. (2004) concluded that ROR2 is essential at multiple sites during development and that the Ror2 -/- mouse provides a suitable model for the study of the underlying developmental malformations in individuals with Robinow syndrome.
In an affected member of a family with brachydactyly type B (BDB1; 113000), Oldridge et al. (2000) found heterozygosity for a 2265C-A transversion in the ROR2 gene, resulting in a tyr755-to-ter mutation.
Hamamy et al. (2006) reported a Jordanian man with brachydactyly type B who had a heterozygous Y755X mutation. He had a severe form of the disease with classic brachydactyly and specific facial features, including prominent nose, high nasal bridge, hypoplastic alae nasi, and high-arched palate. His 3-year-old affected son also had the mutation.
In an affected member of a family with brachydactyly type B (BDB1; 113000), Oldridge et al. (2000) found heterozygosity for a 2246G-A transition in the ROR2 gene, resulting in a trp749-to-ter (W749X) change.
The same W749X substitution was described in a Welsh family, first described by Schott (1978) as having a condition he termed hereditary brachydactyly with nail dysplasia, but the base change in that case was a heterozygous 2247G-A transition (602337.0009).
In an affected member of a family with brachydactyly type B (BDB1; 113000), Oldridge et al. (2000) found a 1-bp deletion, 2249delG, in the ROR2 gene leading to a frameshift at gly750 with an arginine/proline-rich sequence of 23 novel amino acids before the first stop codon. The phenotype also included cutaneous syndactyly.
Lv et al. (2009) reported a Chinese family with a similar phenotype, including cutaneous syndactyly, with a similar mutation (2243delC; 602337.0014).
In 14 patients with recessive Robinow syndrome (RRS1; 268310) from 7 families from Oman, Afzal et al. (2000) identified a gln502-to-ter (Q502X) nonsense mutation in exon 9 of the ROR2 gene that removed the tyrosine kinase domain and all subsequent 3-prime regions.
In 3 Brazilian sibs with autosomal recessive Robinow syndrome (RRS1; 268310), Afzal et al. (2000) identified a 550C-T transition in exon 5 of the ROR2 gene, resulting in an arg184-to-cys (R184C) missense change.
In a 40-year-old German man with autosomal recessive Robinow syndrome, Tufan et al. (2005) identified compound heterozygosity for the R184C mutation and a 355C-T transition in exon 3 of the ROR2 gene, resulting in an arg119-to-ter (R119X; 602337.0011) substitution in the Ig domain. The nonconsanguineous father and mother were heterozygous for R184C and R119X, respectively.
By bioinformatic analysis and immunoprecipitation studies, Chen et al. (2005) showed that endoplasmic reticulum (ER) retention was the mechanism underlying RRS1. Specifically, mutant alleles of ROR2, including the R184C mutation, that are associated with RRS1 were retained within the ER, whereas wildtype and nonpathogenic alleles were exported to the plasma membrane.
In a family of Turkish descent with autosomal recessive Robinow syndrome (RRS1; 268310), van Bokhoven et al. (2000) demonstrated that the ROR2 gene in affected individuals carried a homozygous nonsense mutation, trp720 to ter (W720X).
In 3 consanguineous Turkish families with autosomal recessive Robinow syndrome (RRS1; 268310), van Bokhoven et al. (2000) demonstrated that affected members carried an arg205-to-ter (R205X) nonsense mutation in the ROR2 gene.
In an extensive Turkish kindred, Schwabe et al. (2000) demonstrated that type B brachydactyly (BDB1; 113000) was caused by a heterozygous 5-bp deletion (1321delCGGCG) in exon 8 of the ROR2 gene, proximal to the tyrosine kinase domain, resulting in a frameshift and a stop codon after 14 amino acids. One individual in this family, born of consanguineous parents who both had BDB1, was homozygous for the 5-bp deletion. He had particularly severe skeletal manifestations and a ventricular septal defect. His phenotype resembled an extreme form of brachydactyly, with extensive aplasia/hypoplasia of the phalanges and metacarpals/metatarsals and absence of nails (see 268310). Vertebral anomalies, brachymelia of the arms, and a ventricular septal defect were features reminiscent of Robinow syndrome, but he lacked the craniofacial features of Robinow syndrome.
In a Welsh family described by Schott (1978) with a disorder he designated hereditary brachydactyly with nail dysplasia (HPND), Bacchelli et al. (2003) found a heterozygous G-to-A transition in exon 9 of the ROR2 gene (2247G-A), which converted amino acid 749 from tryptophan to a premature stop. Contrary to the previous report by Schott (1978), who thought the disorder was distinct from brachydactyly type B1 (BDB1; 113000) due to lack of foot involvement, Bacchelli et al. (2003) found subtle foot involvement and a facial appearance typical of BDB. Typical BDB due to a nonsense mutation in the same codon but resulting from a different base change was reported in a German family with typical BDB by Oldridge et al. (2000); see 602337.0002.
In a 28-year-old Turkish man, born of first-cousin parents, who had autosomal recessive Robinow syndrome (RRS1; 268310), Tufan et al. (2005) identified homozygosity for a 7-bp deletion (1937delACAAGCT) in exon 9 of the ROR2 gene. His parents were both heterozygous for the deletion.
For discussion of the arg119-to-ter (R119X) mutation in the ROR2 gene that was found in compound heterozygous state in a patient with autosomal recessive Robinow syndrome (RRS1; 268310) by Tufan et al. (2005), see 602337.0005.
In 2 sib pairs with Robinow syndrome (RRS1; 268310) from the same extended family, Brunetti-Pierri et al. (2008) identified homozygosity for an 8,851-bp deletion encompassing exons 6 and 7 of the ROR2 gene, with the centromeric breakpoint between nucleotides 93529881 and 93529882 on chromosome 9 and the telomeric breakpoint between nucleotides 93538732 and 93538733. All 4 unaffected parents were heterozygous for the deletion. The patients demonstrated intrafamilial variability with respect to cleft lip, cleft palate, and cardiac abnormalities. One of the sibs presented at age 17 with back pain, and spine MRI revealed a thoracic syringomyelia, which had not previously been reported in Robinow syndrome.
In 10 affected and 3 unaffected members of a large Turkish family with a mild brachydactyly type B1 phenotype (BDB1; 113000), Kjaer et al. (2009) identified a heterozygous 1-bp insertion (1366insC) in exon 9 of the ROR2 gene. The authors stated that this family presented the mildest mutation-positive BDB1 phenotype reported to date, with 3 unaffected ROR2 mutation carriers and only 3 carriers with the typical BDB1 distal reductions.
In affected members of a large Chinese family with brachydactyly type 1 and various degrees of cutaneous syndactyly (BDB1; 113000), Lv et al. (2009) identified a heterozygous 1-bp deletion (2243delC) in exon 9 of the ROR2 gene, predicted to result in a truncated protein with an additional C-terminal polypeptide of 24 residues. Lv et al. (2009) noted that a Portuguese family with a similar phenotype including cutaneous syndactyly had a similar mutation (2249delG; 602337.0003).
Schwarzer et al. (2009) identified homozygosity for a 1324C-T transition in the ROR2 gene, resulting in an arg441-to-ter (R441X) substitution, in a 9-month old Omani child exhibiting features of Robinow syndrome in conjunction with complex, symmetric brachy-syn-polydactyly of the hands and oligodactyly of the feet with absent toes 2 to 4 (see 268310). The Omani parents were healthy, had no features of Robinow syndrome or brachydactyly type B1 (113000), and were distantly related by mothers of the same tribal background. The mutation was located at the same position as a frameshift mutation (602337.0008) causing dominant BDB1.
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