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Stefan Mundlos - One of the best experts on this subject based on the ideXlab platform.
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PATTERNS & PHENOTYPES Cloning and Expression Pattern of Chicken Ror2 and Functional Characterization of Truncating Mutations in Brachydactyly Type B and Robinow Syndrome
2016Co-Authors: Sigmar Stricker, Norbert Brieske, Nicole Verhey Van Wijk, Florian Witte, Kathrin Seidel, Stefan MundlosAbstract:Ror2 is a receptor tyrosine kinase mutated in the human Syndromes Brachydactyly type B (BDB) and recessive Robinow Syndrome (RS). In this study, we used the chick as a model to investigate the role of Ror2 in skeletogenesis and to elucidate the functional consequences of Ror2 mutations. For this purpose, we cloned chicken Ror2 and analyzed its expression pattern at various embryonic stages by in situ hybridization and immunolabeling. We document expression of cRor2 in several organs, including mesonephros, heart, nervous system, intestine and cartilage. The high conservation of expression when compared with the mouse underlines the validity of the chick as a model system. Using replication-competent retroviral vector–mediated overexpression, we analyzed the functional consequences of truncating BDB and RS mutations in the developing chick limb. Overexpression of Ror2 mutants led to a disturbance of growth plate architecture and a severe block of chondrocyte differentiation, demonstrating the functional importance of Ror2 in skeletogenesis. Developmental Dynamics 235:3456–3465, 2006
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a gradient of ror2 protein stability and membrane localization confers brachydactyly type b or Robinow Syndrome phenotypes
Human Molecular Genetics, 2009Co-Authors: Wibke Schwarzer, Florian Witte, Stefan Mundlos, Anna Rajab, Sigmar StrickerAbstract:Mutations in ROR2 cause dominant brachydactyly type B (BDB1) or recessive Robinow Syndrome (RRS), each characterized by a distinct combination of phenotypic features. We here report a novel nonsense mutation in ROR2 (c.1324C>T; p.R441X) causing intracellular protein truncation in a patient exhibiting features of RRS in conjunction with severe recessive brachydactyly. The mutation is located at the same position as a previously described frame shift mutation causing dominant BDB1. To investigate the apparent discrepancy in phenotypic outcome, we analysed ROR2 protein stability and distribution in stably transfected cell lines expressing exact copies of several human RRS and BDB1 intracellular mutations. RRS mutant proteins were less abundant and retained intracellularly, although BDB1 mutants were stable and predominantly located at the cell membrane. The p.R441X mutation showed an intermediate pattern with membrane localization but also high endoplasmic reticulum retention. Furthermore, we observed 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. We propose a model in which the RRS versus the BDB1 phenotype is determined by the relative degree of protein retention/degradation and the amount of mutant protein reaching the plasma membrane.
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Robinow Syndrome phenotypic variability in a family with a novel intragenic ror2 mutation
American Journal of Medical Genetics Part A, 2008Co-Authors: Nicola Brunettipierri, Stefan Mundlos, Daniela Del Gaudio, Hartmut Peters, Henri Justino, Clauseric Ott, Carlos A. BacinoAbstract:Robinow Syndrome comprises dysmorphic facial features, short stature, brachymesomelia, segmental spine defects, and genital hypoplasia. The range of severity in this disorder is broad. We report on the clinical and molecular findings of two sib pairs from the same extended family with Robinow Syndrome due to a novel intragenic ROR2 deletion involving exons 6 and 7 that could not be detected by sequencing. The affected individuals exhibited variability with respect to the cleft lip, cleft palate, and cardiac findings and for the presence in one of the patients of syringomyelia, which has not been previously reported in Robinow Syndrome.
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cloning and expression pattern of chicken ror2 and functional characterization of truncating mutations in brachydactyly type b and Robinow Syndrome
Developmental Dynamics, 2006Co-Authors: Sigmar Stricker, Norbert Brieske, Nicole Verhey Van Wijk, Florian Witte, Kathrin Seidel, Stefan MundlosAbstract:Ror2 is a receptor tyrosine kinase mutated in the human Syndromes Brachydactyly type B (BDB) and recessive Robinow Syndrome (RS). In this study, we used the chick as a model to investigate the role of Ror2 in skeletogenesis and to elucidate the functional consequences of Ror2 mutations. For this purpose, we cloned chicken Ror2 and analyzed its expression pattern at various embryonic stages by in situ hybridization and immunolabeling. We document expression of cRor2 in several organs, including mesonephros, heart, nervous system, intestine and cartilage. The high conservation of expression when compared with the mouse underlines the validity of the chick as a model system. Using replication-competent retroviral vector-mediated overexpression, we analyzed the functional consequences of truncating BDB and RS mutations in the developing chick limb. Overexpression of Ror2 mutants led to a disturbance of growth plate architecture and a severe block of chondrocyte differentiation, demonstrating the functional importance of Ror2 in skeletogenesis.
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Clinical and molecular characterization of two adults with autosomal recessive Robinow Syndrome.
American journal of medical genetics. Part A, 2005Co-Authors: Fatih Tufan, Kivanc Cefle, Seval Türkmen, Aydin Turkmen, Unal Zorba, Memduh Dursun, Sukru Ozturk, Sukru Palanduz, Tevfik Ecder, Stefan MundlosAbstract:Autosomal recessive Robinow Syndrome is caused by mutations in ROR2 and is characterized by short stature, mesomelic limb shortening, brachydactyly, vertebral abnormalities, and a characteristic “fetal face” dysmorphology. We report the clinical and molecular studies on two adults with this condition. Besides typical skeletal and facial features, one patient developed hydronephrosis, nephrocalcinosis, and renal failure. The second patient had characteristic skeletal manifestations including severe spinal involvement and showed endocrinological abnormalities including elevated gonadotropic hormones. The facial phenotype in both patients remained distinctive into adulthood. Analysis of the ROR2 gene revealed a homozygous c.1937_1943delACAAGCT mutation in Patient 1, and compound heterozygosity for c.355C > T (p.R119X). and c.550C > T (p.R184C) in Patient 2. © 2005 Wiley-Liss, Inc.
Juliana F. Mazzeu - One of the best experts on this subject based on the ideXlab platform.
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Novel pathogenic genomic variants leading to autosomal dominant and recessive Robinow Syndrome.
American journal of medical genetics. Part A, 2020Co-Authors: Chaofan Zhang, Janson J. White, Juliana F. Mazzeu, Shalini N. Jhangiani, Donna M. Muzny, Jesper Eisfeldt, Christopher M. Grochowski, Zeynep Coban Akdemir, Richard A. Gibbs, Anna LindstrandAbstract:Robinow Syndrome (RS) is a genetically heterogeneous disorder characterized by skeletal dysplasia and a distinctive facial appearance. Previous studies have revealed locus heterogeneity with rare variants in DVL1, DVL3, FZD2, NXN, ROR2, and WNT5A underlying the etiology of RS. The aforementioned "Robinow-associated genes" and their gene products all play a role in the WNT/planar cell polarity signaling pathway. We performed gene-targeted Sanger sequencing, exome sequencing, genome sequencing, and array comparative genomic hybridization on four subjects with a clinical diagnosis of RS who had not had prior DNA testing. Individuals in our cohort were found to carry pathogenic or likely pathogenic variants in three RS related genes: DVL1, ROR2, and NXN. One subject was found to have a nonsense variant (c.817C > T [p.Gln273*]) in NXN in trans with an ~1 Mb telomeric deletion on chromosome 17p containing NXN, which supports our contention that biallelic NXN variant alleles are responsible for a novel autosomal recessive RS locus. These findings provide increased understanding of the role of WNT signaling in skeletal development and maintenance. These data further support the hypothesis that dysregulation of the noncanonical WNT pathway in humans gives rise to RS.
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Neurocognitive, adaptive, and psychosocial functioning in individuals with Robinow Syndrome
American journal of medical genetics. Part A, 2020Co-Authors: David D. Schwartz, V. Reid Sutton, Claudia M.b. Carvalho, Juliana F. Mazzeu, Rachel H. Fein, Marni E. AxelradAbstract:It has been estimated that 10-15% of people with Robinow Syndrome (RS) show delayed development, but no studies have formally assessed developmental domains. The objective of this study is to provide the first description of cognitive, adaptive, and psychological functioning in RS. Thirteen participants (10 males) aged 4-51 years were seen for neuropsychological screening. Eight had autosomal-dominant RS (DVL1, n = 5; WNT5A, n = 3), four had autosomal-recessive RS (NXN, n = 2; ROR2, n = 2), and one had a mutation on an RS candidate gene (GPC4). Participants completed measures of intellectual, fine-motor, adaptive, executive, and psychological functioning. Findings indicated generally average intellectual functioning and low-average visuomotor skills. Adaptive functioning was average in autosomal-recessive RS (RRS) but low average in autosomal-dominant RS (DRS). Parent-report indicated executive dysfunction and attention problems in 4/8 children, 3/4 of whom had a DVL1 variant; adult self-report did not indicate similar difficulties. Learning disabilities were also reported in 4/8 individuals with DRS, 3/4 of whom had a DVL1 variant. Peer problems were reported for a majority of participants, many of whom also reported emotional concerns. Altogether, the findings indicate average neurocognitive functioning in RRS. In contrast, DRS, especially DVL1 pathogenic alleles, may confer specific risk for neurodevelopmental disability.
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DVL3 Alleles Resulting in a -1 Frameshift of the Last Exon Mediate Autosomal-Dominant Robinow Syndrome
American journal of human genetics, 2016Co-Authors: Janson J. White, Juliana F. Mazzeu, Alexander Hoischen, Yavuz Bayram, Marjorie Withers, Alper Gezdirici, Virginia Kimonis, Marloes Steehouwer, Shalini N. Jhangiani, Donna M. MuznyAbstract:Robinow Syndrome is a rare congenital disorder characterized by mesomelic limb shortening, genital hypoplasia, and distinctive facial features. Recent reports have identified, in individuals with dominant Robinow Syndrome, a specific type of variant characterized by being uniformly located in the penultimate exon of DVL1 and resulting in a −1 frameshift allele with a premature termination codon that escapes nonsense-mediated decay. Here, we studied a cohort of individuals who had been clinically diagnosed with Robinow Syndrome but who had not received a molecular diagnosis from variant studies of DVL1, WNT5A, and ROR2. Because of the uniform location of frameshift variants in DVL1-mediated Robinow Syndrome and the functional redundancy of DVL1, DVL2, and DVL3, we elected to pursue direct Sanger sequencing of the penultimate exon of DVL1 and its paralogs DVL2 and DVL3 to search for potential disease-associated variants. Remarkably, targeted sequencing identified five unrelated individuals harboring heterozygous, de novo frameshift variants in DVL3, including two splice acceptor mutations and three 1 bp deletions. Similar to the variants observed in DVL1-mediated Robinow Syndrome, all variants in DVL3 result in a −1 frameshift, indicating that these highly specific alterations might be a common cause of dominant Robinow Syndrome. Here, we review the current knowledge of these peculiar variant alleles in DVL1- and DVL3-mediated Robinow Syndrome and further elucidate the phenotypic features present in subjects with DVL1 and DVL3 frameshift mutations.
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Autosomal Dominant Robinow Syndrome
2015Co-Authors: Maian Roifman, Juliana F. Mazzeu, Han G. Brunner, Jamie L. Lohr, David ChitayatAbstract:Clinical characteristics Autosomal dominant Robinow Syndrome (ADRS) is characterized by skeletal findings (short stature, mesomelic limb shortening predominantly of the upper limbs, and brachydactyly), genital abnormalities (in males: micropenis / webbed penis, hypoplastic scrotum, cryptorchidism; in females: hypoplastic clitoris and labia majora), dysmorphic facial features (widely spaced and prominent eyes, frontal bossing, anteverted nares, midface retrusion), dental abnormalities (including malocclusion, crowding, hypodontia, late eruption of permanent teeth), bilobed tongue, and occasional prenatal macrocephaly that persists postnatally. Less common findings include renal anomalies, radial head dislocation, vertebral abnormalities such as hemivertebrae and scoliosis, nail dysplasia, cardiac defects, cleft lip/palate, and (rarely) cognitive delay. When present, cardiac defects are a major cause of morbidity and mortality. A variant of Robinow Syndrome, associated with osteosclerosis and caused by a heterozygous pathogenic variant in DVL1, is characterized by normal stature, persistent macrocephaly, increased bone mineral density with skull osteosclerosis, and hearing loss, in addition to the typical features described above. Diagnosis/testing The diagnosis of autosomal dominant Robinow Syndrome is established in a proband with typical suggestive findings and/or by the identification of a heterozygous pathogenic variant in DVL1, DVL3, or WNT5A through molecular genetic testing. Management Treatment of manifestations: Corrective surgeries as needed for cryptorchidism, abnormal penile insertion / penoscrotal position, and cleft lip/palate. Hormone therapy may be helpful for males with micropenis. Orthodontic treatment is typically required. Surveillance: Measurement of head circumference regularly in infancy and throughout childhood. Developmental assessment every three months in infancy and every six months to one year thereafter, or more frequently as needed if cognitive delays are identified. Dental evaluation every six to 12 months or as recommended. Periodic hearing assessments in childhood. Regular cardiac and renal assessment as needed by respective specialists if abnormalities are identified. Evaluation of relatives at risk: Evaluation of the sibs of a proband in order to identify as early as possible those who would benefit from institution of treatment and surveillance. Pregnancy management: Pregnancy in affected women appears to be generally uncomplicated. For an affected fetus, cesarean section may be required for abnormal presentation and/or cephalopelvic disproportion. Genetic counseling ADRS is inherited in an autosomal dominant manner. A proband may have the disorder as a result of either an inherited or de novo pathogenic variant. Each child of an individual with ADRS has a 50% chance of inheriting the pathogenic variant; however, the severity of the clinical manifestations cannot be predicted from the results of molecular genetic testing. Prenatal testing for pregnancies at increased risk is possible if the DVL1, DVL3, or WNT5A pathogenic variant has been identified in an affected family member.
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DVL1 Frameshift Mutations Clustering in the Penultimate Exon Cause Autosomal-Dominant Robinow Syndrome
American journal of human genetics, 2015Co-Authors: Janson J. White, Jorge M. Saraiva, Juliana F. Mazzeu, Alexander Hoischen, Shalini N. Jhangiani, Tomasz Gambin, Michele Calijorne Alcino, Samantha Penney, Hanne Hove, Flemming SkovbyAbstract:Robinow Syndrome is a genetically heterogeneous disorder characterized by mesomelic limb shortening, genital hypoplasia, and distinctive facial features and for which both autosomal-recessive and autosomal-dominant inheritance patterns have been described. Causative variants in the non-canonical signaling gene WNT5A underlie a subset of autosomal-dominant Robinow Syndrome (DRS) cases, but most individuals with DRS remain without a molecular diagnosis. We performed whole-exome sequencing in four unrelated DRS-affected individuals without coding mutations in WNT5A and found heterozygous DVL1 exon 14 mutations in three of them. Targeted Sanger sequencing in additional subjects with DRS uncovered DVL1 exon 14 mutations in five individuals, including a pair of monozygotic twins. In total, six distinct frameshift mutations were found in eight subjects, and all were heterozygous truncating variants within the penultimate exon of DVL1. In five families in which samples from unaffected parents were available, the variants were demonstrated to represent de novo mutations. All variant alleles are predicted to result in a premature termination codon within the last exon, escape nonsense-mediated decay (NMD), and most likely generate a C-terminally truncated protein with a distinct −1 reading-frame terminus. Study of the transcripts extracted from affected subjects’ leukocytes confirmed expression of both wild-type and variant alleles, supporting the hypothesis that mutant mRNA escapes NMD. Genomic variants identified in our study suggest that truncation of the C-terminal domain of DVL1, a protein hypothesized to have a downstream role in the Wnt-5a non-canonical pathway, is a common cause of DRS.
Ali R Afzal - One of the best experts on this subject based on the ideXlab platform.
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novel Robinow Syndrome causing mutations in the proximal region of the frizzled like domain of ror2 are retained in the endoplasmic reticulum
Human Genetics, 2007Co-Authors: Bassam R Ali, Steve Jeffery, Neha Patel, Lorna Tinworth, Nagwa A Meguid, Michael A Patton, Ali R AfzalAbstract:ROR2 is a member of the cell surface receptor tyrosine kinase (RTKs) family of proteins and is involved in the developmental morphogenesis of the skeletal, cardiovascular and genital systems. Mutations in ROR2 have been shown to cause two distinct human disorders, autosomal recessive Robinow Syndrome and dominantly inherited Brachydactyly type B. The recessive form of Robinow Syndrome is a disorder caused by loss-of-function mutations whereas Brachydactyly type B is a dominant disease and is presumably caused by gain-of-function mutations in the same gene. We have previously established that all the missense mutations causing Robinow Syndrome in ROR2 are retained in the endoplasmic reticulum and therefore concluded that their loss of function is due to a defect in their intracellular trafficking. These mutations were in the distal portion of the frizzled-like cysteine rich domain and kringle domain. Here we report the identification of two novel mutations in the frizzled-like cysteine-rich domain of ROR2 causing Robinow Syndrome. We establish the retention of the mutated proteins in the endoplasmic reticulum of HeLa cells and therefore failure to reach the plasma membrane. The clustering of Robinow-causing mutations in the extracellular frizzled-like cysteine-rich domain of ROR2 suggests a stringent requirement for the correct folding of this domain prior to export of ROR2 from the endoplasmic reticulum to the plasma membrane.
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one gene two phenotypes ror2 mutations in autosomal recessive Robinow Syndrome and autosomal dominant brachydactyly type b
Human Mutation, 2003Co-Authors: Ali R Afzal, Steve JefferyAbstract:Autosomal recessive Robinow Syndrome (RRS) is a severe skeletal dysplasia with short stature, generalized limb shortening, segmental defects of the spine, brachydactyly, and a dysmorphic facial appearance. The gene encoding receptor orphan receptor tyrosine kinase 2 (ROR2) is located on chromosome 9q22 and homozygous loss-of-function mutations in this gene are responsible for RRS. Moreover, knocking out the mouse Ror2 gene causes mesomelic dwarfism in the homozygous state, with almost identical features to recessive Robinow Syndrome. The protein product of this gene is a cell membrane receptor, containing distinct motifs including an immunoglobulin-like (Ig) domain, a Frizzled-like cysteine-rich domain (FRZ or CRD), and a kringle domain (KD) in the extracellular region; and an intracellular region with tyrosine kinase (TK), serine/threonine-rich, and proline-rich structures. The extracellular motifs of the ROR2 protein are known to be involved in protein–protein interactions. The tyrosine kinase domain is involved in an as yet uncharacterized signaling pathway. Interestingly, heterozygous mutations in ROR2 have recently been shown to give rise to autosomal dominant brachydactyly type B1 (BDB1). This condition is characterized by terminal deficiency of fingers and toes. A variety of mutations have been reported in ROR2. Here, these genetic defects are compiled and possible genotype–phenotype correlations are discussed. Hum Mutat 22:1–11, 2003. © 2003 Wiley-Liss, Inc.
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Linkage of recessive Robinow Syndrome to a 4 cM interval on chromosome 9q22.
Human genetics, 2000Co-Authors: Ali R Afzal, Anna Rajab, Michael A Patton, Christiane Fenske, Andrew H. Crosby, N. Lahiri, E. Ternes-pereira, Victoria Murday, Richard S. Houlston, Stephen JefferyAbstract:Autosomal recessive Robinow Syndrome is a form of mesomelic dwarfism with multiple rib and vertebral anomalies. Using autozygosity mapping we have identified a genetic locus (RBNW1) for this Syndrome at chromosome 9q22 in seven consanguineous families from Oman. Our results indicate that the gene lies within a 4 cM region between markers D9S1836 and D9S1803 (maximum multipoint LOD score 12.3). In addition, we have analysed two non-Omani families with autosomal recessive Robinow and found no genetic heterogeneity.
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Recessive Robinow Syndrome, allelic to dominant brachydactyly type B, is caused by mutation of ROR2
Nature genetics, 2000Co-Authors: Ali R Afzal, Anna Rajab, Michael A Patton, Christiane Fenske, Victoria Murday, Michael Oldridge, N Elanko, Eliana Ternes-pereira, Beyhan Tüysüz, Andrew O.m. WilkieAbstract:The autosomal recessive form of Robinow Syndrome (RRS; MIM 268310) is a severe skeletal dysplasia with generalized limb bone shortening, segmental defects of the spine, brachydactyly and a dysmorphic facial appearance. We previously mapped the gene mutated in RRS to chromosome 9q22 (ref. 4), a region that overlaps the locus for autosomal dominant brachydactyly type B (refs 5,6). The recent identification of ROR2, encoding an orphan receptor tyrosine kinase, as the gene mutated in brachydactyly type B (BDB1; ref. 7) and the mesomelic dwarfing in mice homozygous for a lacZ and/or a neo insertion into Ror2 (refs 8,9) made this gene a candidate for RRS. Here we report homozygous missense mutations in both intracellular and extracellular domains of ROR2 in affected individuals from 3 unrelated consanguineous families, and a nonsense mutation that removes the tyrosine kinase domain and all subsequent 3' regions of the gene in 14 patients from 7 families from Oman. The nature of these mutations suggests that RRS is caused by loss of ROR2 activity. The identification of mutations in three distinct domains (containing Frizzled-like, kringle and tyrosine kinase motifs) indicates that these are all essential for ROR2 function.
Janson J. White - One of the best experts on this subject based on the ideXlab platform.
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Novel pathogenic genomic variants leading to autosomal dominant and recessive Robinow Syndrome.
American journal of medical genetics. Part A, 2020Co-Authors: Chaofan Zhang, Janson J. White, Juliana F. Mazzeu, Shalini N. Jhangiani, Donna M. Muzny, Jesper Eisfeldt, Christopher M. Grochowski, Zeynep Coban Akdemir, Richard A. Gibbs, Anna LindstrandAbstract:Robinow Syndrome (RS) is a genetically heterogeneous disorder characterized by skeletal dysplasia and a distinctive facial appearance. Previous studies have revealed locus heterogeneity with rare variants in DVL1, DVL3, FZD2, NXN, ROR2, and WNT5A underlying the etiology of RS. The aforementioned "Robinow-associated genes" and their gene products all play a role in the WNT/planar cell polarity signaling pathway. We performed gene-targeted Sanger sequencing, exome sequencing, genome sequencing, and array comparative genomic hybridization on four subjects with a clinical diagnosis of RS who had not had prior DNA testing. Individuals in our cohort were found to carry pathogenic or likely pathogenic variants in three RS related genes: DVL1, ROR2, and NXN. One subject was found to have a nonsense variant (c.817C > T [p.Gln273*]) in NXN in trans with an ~1 Mb telomeric deletion on chromosome 17p containing NXN, which supports our contention that biallelic NXN variant alleles are responsible for a novel autosomal recessive RS locus. These findings provide increased understanding of the role of WNT signaling in skeletal development and maintenance. These data further support the hypothesis that dysregulation of the noncanonical WNT pathway in humans gives rise to RS.
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DVL3 Alleles Resulting in a -1 Frameshift of the Last Exon Mediate Autosomal-Dominant Robinow Syndrome
American journal of human genetics, 2016Co-Authors: Janson J. White, Juliana F. Mazzeu, Alexander Hoischen, Yavuz Bayram, Marjorie Withers, Alper Gezdirici, Virginia Kimonis, Marloes Steehouwer, Shalini N. Jhangiani, Donna M. MuznyAbstract:Robinow Syndrome is a rare congenital disorder characterized by mesomelic limb shortening, genital hypoplasia, and distinctive facial features. Recent reports have identified, in individuals with dominant Robinow Syndrome, a specific type of variant characterized by being uniformly located in the penultimate exon of DVL1 and resulting in a −1 frameshift allele with a premature termination codon that escapes nonsense-mediated decay. Here, we studied a cohort of individuals who had been clinically diagnosed with Robinow Syndrome but who had not received a molecular diagnosis from variant studies of DVL1, WNT5A, and ROR2. Because of the uniform location of frameshift variants in DVL1-mediated Robinow Syndrome and the functional redundancy of DVL1, DVL2, and DVL3, we elected to pursue direct Sanger sequencing of the penultimate exon of DVL1 and its paralogs DVL2 and DVL3 to search for potential disease-associated variants. Remarkably, targeted sequencing identified five unrelated individuals harboring heterozygous, de novo frameshift variants in DVL3, including two splice acceptor mutations and three 1 bp deletions. Similar to the variants observed in DVL1-mediated Robinow Syndrome, all variants in DVL3 result in a −1 frameshift, indicating that these highly specific alterations might be a common cause of dominant Robinow Syndrome. Here, we review the current knowledge of these peculiar variant alleles in DVL1- and DVL3-mediated Robinow Syndrome and further elucidate the phenotypic features present in subjects with DVL1 and DVL3 frameshift mutations.
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DVL1 Frameshift Mutations Clustering in the Penultimate Exon Cause Autosomal-Dominant Robinow Syndrome
American journal of human genetics, 2015Co-Authors: Janson J. White, Jorge M. Saraiva, Juliana F. Mazzeu, Alexander Hoischen, Shalini N. Jhangiani, Tomasz Gambin, Michele Calijorne Alcino, Samantha Penney, Hanne Hove, Flemming SkovbyAbstract:Robinow Syndrome is a genetically heterogeneous disorder characterized by mesomelic limb shortening, genital hypoplasia, and distinctive facial features and for which both autosomal-recessive and autosomal-dominant inheritance patterns have been described. Causative variants in the non-canonical signaling gene WNT5A underlie a subset of autosomal-dominant Robinow Syndrome (DRS) cases, but most individuals with DRS remain without a molecular diagnosis. We performed whole-exome sequencing in four unrelated DRS-affected individuals without coding mutations in WNT5A and found heterozygous DVL1 exon 14 mutations in three of them. Targeted Sanger sequencing in additional subjects with DRS uncovered DVL1 exon 14 mutations in five individuals, including a pair of monozygotic twins. In total, six distinct frameshift mutations were found in eight subjects, and all were heterozygous truncating variants within the penultimate exon of DVL1. In five families in which samples from unaffected parents were available, the variants were demonstrated to represent de novo mutations. All variant alleles are predicted to result in a premature termination codon within the last exon, escape nonsense-mediated decay (NMD), and most likely generate a C-terminally truncated protein with a distinct −1 reading-frame terminus. Study of the transcripts extracted from affected subjects’ leukocytes confirmed expression of both wild-type and variant alleles, supporting the hypothesis that mutant mRNA escapes NMD. Genomic variants identified in our study suggest that truncation of the C-terminal domain of DVL1, a protein hypothesized to have a downstream role in the Wnt-5a non-canonical pathway, is a common cause of DRS.
Sigmar Stricker - One of the best experts on this subject based on the ideXlab platform.
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PATTERNS & PHENOTYPES Cloning and Expression Pattern of Chicken Ror2 and Functional Characterization of Truncating Mutations in Brachydactyly Type B and Robinow Syndrome
2016Co-Authors: Sigmar Stricker, Norbert Brieske, Nicole Verhey Van Wijk, Florian Witte, Kathrin Seidel, Stefan MundlosAbstract:Ror2 is a receptor tyrosine kinase mutated in the human Syndromes Brachydactyly type B (BDB) and recessive Robinow Syndrome (RS). In this study, we used the chick as a model to investigate the role of Ror2 in skeletogenesis and to elucidate the functional consequences of Ror2 mutations. For this purpose, we cloned chicken Ror2 and analyzed its expression pattern at various embryonic stages by in situ hybridization and immunolabeling. We document expression of cRor2 in several organs, including mesonephros, heart, nervous system, intestine and cartilage. The high conservation of expression when compared with the mouse underlines the validity of the chick as a model system. Using replication-competent retroviral vector–mediated overexpression, we analyzed the functional consequences of truncating BDB and RS mutations in the developing chick limb. Overexpression of Ror2 mutants led to a disturbance of growth plate architecture and a severe block of chondrocyte differentiation, demonstrating the functional importance of Ror2 in skeletogenesis. Developmental Dynamics 235:3456–3465, 2006
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a gradient of ror2 protein stability and membrane localization confers brachydactyly type b or Robinow Syndrome phenotypes
Human Molecular Genetics, 2009Co-Authors: Wibke Schwarzer, Florian Witte, Stefan Mundlos, Anna Rajab, Sigmar StrickerAbstract:Mutations in ROR2 cause dominant brachydactyly type B (BDB1) or recessive Robinow Syndrome (RRS), each characterized by a distinct combination of phenotypic features. We here report a novel nonsense mutation in ROR2 (c.1324C>T; p.R441X) causing intracellular protein truncation in a patient exhibiting features of RRS in conjunction with severe recessive brachydactyly. The mutation is located at the same position as a previously described frame shift mutation causing dominant BDB1. To investigate the apparent discrepancy in phenotypic outcome, we analysed ROR2 protein stability and distribution in stably transfected cell lines expressing exact copies of several human RRS and BDB1 intracellular mutations. RRS mutant proteins were less abundant and retained intracellularly, although BDB1 mutants were stable and predominantly located at the cell membrane. The p.R441X mutation showed an intermediate pattern with membrane localization but also high endoplasmic reticulum retention. Furthermore, we observed 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. We propose a model in which the RRS versus the BDB1 phenotype is determined by the relative degree of protein retention/degradation and the amount of mutant protein reaching the plasma membrane.
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cloning and expression pattern of chicken ror2 and functional characterization of truncating mutations in brachydactyly type b and Robinow Syndrome
Developmental Dynamics, 2006Co-Authors: Sigmar Stricker, Norbert Brieske, Nicole Verhey Van Wijk, Florian Witte, Kathrin Seidel, Stefan MundlosAbstract:Ror2 is a receptor tyrosine kinase mutated in the human Syndromes Brachydactyly type B (BDB) and recessive Robinow Syndrome (RS). In this study, we used the chick as a model to investigate the role of Ror2 in skeletogenesis and to elucidate the functional consequences of Ror2 mutations. For this purpose, we cloned chicken Ror2 and analyzed its expression pattern at various embryonic stages by in situ hybridization and immunolabeling. We document expression of cRor2 in several organs, including mesonephros, heart, nervous system, intestine and cartilage. The high conservation of expression when compared with the mouse underlines the validity of the chick as a model system. Using replication-competent retroviral vector-mediated overexpression, we analyzed the functional consequences of truncating BDB and RS mutations in the developing chick limb. Overexpression of Ror2 mutants led to a disturbance of growth plate architecture and a severe block of chondrocyte differentiation, demonstrating the functional importance of Ror2 in skeletogenesis.
