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Elizabeth C. Engle - One of the best experts on this subject based on the ideXlab platform.
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Congenital Fibrosis of the Extraocular Muscles
Seminars in Ophthalmology, 2020Co-Authors: Gena Heidary, Elizabeth C. Engle, David G. HunterAbstract:Congenital fibrosis of the extraocular muscles (CFEOM) is a strabismus syndrome characterized by non-progressive, restrictive ophthalmoplegia of the extraocular muscles and congenital blepharoptosis. Three clinical phenotypes for familial CFEOM (CFEOM1, 2, and 3) have been delineated, for which two genes have been identified to date: KIF21A for CFEOM1 and 3 and PHOX2A/ARIX for CFEOM2. Insights gained from molecular genetics have strengthened the hypothesis that CFEOM results from the dysinnervation of the extraocular muscles supplied by the oculomotor and/or trochlear nerves. Continued study of this syndrome should help to further elucidate the pathogenesis of eye movement disorders.
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Outcomes of strabismus surgery in genetically confirmed congenital fibrosis of the extraocular muscles.
Journal of Aapos, 2019Co-Authors: Gena Heidary, Elizabeth C. Engle, Sarah Mackinnon, Alexandra T. Elliott, Brenda J. Barry, David G. HunterAbstract:Abstract Purpose To detail surgical strategy and strabismus outcomes in a genetically defined cohort of patients with congenital fibrosis of the extraocular muscles (CFEOM). Methods A total of 13 patients with genetically confirmed CFEOM (via genetic testing for mutations in KIF21A, PHOX2A, and TUBB3) were retrospectively identified after undergoing strabismus surgery at Boston Children’s Hospital and surgical outcomes were compared. Results Age at first surgery ranged from 11 months to 63 years, with an average of 3 strabismus procedures per patient. Ten patients had CFEOM1, of whom 9 had the KIF21A R954W amino acid (AA) substitution and 1 had the M947T AA substitution. Of the 3 with CFEOM3, 2 had the TUBB3 E410K AA substitution, and 1 had a previously unreported E410V AA substitution. CFEOM1 patients all underwent at least 1 procedure to address chin-up posture. Chin-up posture improved from 24° ± 8° before surgery to 10.0° ± 8° postoperatively (P Conclusions CFEOM is a complex strabismus disorder for which surgical management is difficult. Despite an aggressive surgical approach, multiple procedures may be necessary to achieve a desirable surgical effect. Knowledge of the underlying genetic diagnosis may help to inform surgical management.
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Ocular congenital cranial dysinnervation disorders (CCDDs): insights into axon growth and guidance
Human Molecular Genetics, 2017Co-Authors: Mary C. Whitman, Elizabeth C. EngleAbstract:Unraveling the genetics of the paralytic strabismus syndromes known as congenital cranial dysinnervation disorders (CCDDs) is both informing physicians and their patients and broadening our understanding of development of the ocular motor system. Genetic mutations underlying ocular CCDDs alter either motor neuron specification or motor nerve development, and highlight the importance of modulations of cell signaling, cytoskeletal transport, and microtubule dynamics for axon growth and guidance. Here we review recent advances in our understanding of two CCDDs, congenital fibrosis of the extraocular muscles (CFEOM) and Duane retraction syndrome (DRS), and discuss what they have taught us about mechanisms of axon guidance and selective vulnerability. CFEOM presents with congenital ptosis and restricted eye movements, and can be caused by heterozygous missense mutations in the kinesin motor protein KIF21A or in the β-tubulin isotypes TUBB3 or TUBB2B. CFEOM-causing mutations in these genes alter protein function and result in axon growth and guidance defects. DRS presents with inability to abduct one or both eyes. It can be caused by decreased function of several transcription factors critical for abducens motor neuron identity, including MAFB, or by heterozygous missense mutations in CHN1, which encodes α2-chimaerin, a Rac-GAP GTPase that affects cytoskeletal dynamics. Examination of the orbital innervation in mice lacking Mafb has established that the stereotypical misinnervation of the lateral rectus by fibers of the oculomotor nerve in DRS is secondary to absence of the abducens nerve. Studies of a CHN1 mouse model have begun to elucidate mechanisms of selective vulnerability in the nervous system.
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spatiotemporal expression pattern of KIF21A during normal embryonic development and in congenital fibrosis of the extraocular muscles type 1 cfeom1
Gene Expression Patterns, 2012Co-Authors: Jigar Desai, Koki Yamada, Marie Pia Rogines Velo, Lynne M Overman, Elizabeth C. EngleAbstract:Abstract Congenital fibrosis of the extraocular muscles type 1 (CFEOM1) is a rare inherited strabismus syndrome characterized by non-progressive ophthalmoplegia. We previously identified that CFEOM1 results from heterozygous missense mutations in KIF21A, which encodes a kinesin motor protein. Here we evaluate the expression pattern of KIF21A in human brain and muscles of control and CFEOM1 patients, and during human and mouse embryonic development. KIF21A is expressed in the cell bodies, axons, and dendrites of many neuronal populations including those in the hippocampus, cerebral cortex, cerebellum, striatum, and motor neurons of the oculomotor, trochlear, and abducens nuclei from early development into maturity, and its spatial distribution is not altered in the CFEOM1 tissues available for study. Multiple splice isoforms of KIF21A are identified in human fetal brain, but none of the reported CFEOM1 mutations are located in or near the alternatively spliced exons. KIF21A immunoreactivity is also observed in extraocular and skeletal muscle biopsies of control and CFEOM1 patients, where it co-localizes with triadin, a marker of the excitation–contractile coupling system. The diffuse and widespread expression of KIF21A in the developing human and mouse central and peripheral nervous system as well as in extraocular muscle does not account for the restricted ocular phenotype observed in CFEOM1, nor does it permit the formal exclusion of a myogenic etiology based on expression patterns alone.
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KIF21A mutations in two chinese families with congenital fibrosis of the extraocular muscles cfeom
Molecular Vision, 2010Co-Authors: Xian Yang, Elizabeth C. Engle, Caroline Andrews, Koki Yamada, Bradley J Katz, Hongzai Guan, Lifei Wang, Guiqiu Zhao, Haoyu Chen, Zongzhong TongAbstract:Purpose: Two Chinese families (XT and YT) with congenital fibrosis of the extraocular muscles (CFEOM) were identified. The purpose of this study was to determine if previously described Homo sapiens kinesin family member 21A (KIF21A) mutations were responsible for CFEOM in these two Chinese pedigrees. Methods: Clinical characterization and genetic studies were performed. Microsatellite genotyping for linkage to the CFEOM1 and CFEOM3 loci was performed. The probands were screened for KIF21A mutations by bidirectional direct sequencing. Once a mutation was detected in the proband, all other participating family members and 100 unrelated control normal individuals were screened for the mutation. Results: All affected individuals in family XT shared the common manifestations of CFEOM1. Family YT had two affected individuals, a mother and a daughter. The daughter had CFEOM1, while her mother never had congential ptosis but did have limited extraocular movements status post strabismus surgery. Haplotype analysis revealed that pedigree XT was linked to the 12q CFEOM1 locus and the affected memberes harbored the second most common missense mutation in KIF21A (2,861G>A, R954Q). Family YT harbored the most common missense de novo mutation in KIF21A (2,860C>T, R954W). Both of these mutations have been previously described. Conclusions: The observation of these two KIF21A mutations in a Chinese pedigree underscores the homogeneity of these mutations as a cause of CFEOM1 and CFEOM3 across ethnic divisions.
Caroline Andrews - One of the best experts on this subject based on the ideXlab platform.
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KIF21A mutations in two chinese families with congenital fibrosis of the extraocular muscles cfeom
Molecular Vision, 2010Co-Authors: Xian Yang, Elizabeth C. Engle, Caroline Andrews, Koki Yamada, Bradley J Katz, Hongzai Guan, Lifei Wang, Guiqiu Zhao, Haoyu Chen, Zongzhong TongAbstract:Purpose: Two Chinese families (XT and YT) with congenital fibrosis of the extraocular muscles (CFEOM) were identified. The purpose of this study was to determine if previously described Homo sapiens kinesin family member 21A (KIF21A) mutations were responsible for CFEOM in these two Chinese pedigrees. Methods: Clinical characterization and genetic studies were performed. Microsatellite genotyping for linkage to the CFEOM1 and CFEOM3 loci was performed. The probands were screened for KIF21A mutations by bidirectional direct sequencing. Once a mutation was detected in the proband, all other participating family members and 100 unrelated control normal individuals were screened for the mutation. Results: All affected individuals in family XT shared the common manifestations of CFEOM1. Family YT had two affected individuals, a mother and a daughter. The daughter had CFEOM1, while her mother never had congential ptosis but did have limited extraocular movements status post strabismus surgery. Haplotype analysis revealed that pedigree XT was linked to the 12q CFEOM1 locus and the affected memberes harbored the second most common missense mutation in KIF21A (2,861G>A, R954Q). Family YT harbored the most common missense de novo mutation in KIF21A (2,860C>T, R954W). Both of these mutations have been previously described. Conclusions: The observation of these two KIF21A mutations in a Chinese pedigree underscores the homogeneity of these mutations as a cause of CFEOM1 and CFEOM3 across ethnic divisions.
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Three novel mutations in KIF21A highlight the importance of the third coiled-coil stalk domain in the etiology of CFEOM1
BMC Genetics, 2007Co-Authors: Wai-man Chan, David G. Hunter, Caroline Andrews, Laryssa Dragan, Douglas Fredrick, Linlea Armstrong, Christopher Lyons, Michael T Geraghty, Ahmad Yazdani, Elias I TraboulsiAbstract:Background Congenital fibrosis of the extraocular muscles types 1 and 3 (CFEOM1/CFEOM3) are autosomal dominant strabismus disorders that appear to result from maldevelopment of ocular nuclei and nerves. We previously reported that most individuals with CFEOM1 and rare individuals with CFEOM3 harbor heterozygous mutations in KIF21A . KIF21A encodes a kinesin motor involved in anterograde axonal transport, and the familial and de novo mutations reported to date predictably alter one of only a few KIF21A amino acids – three within the third coiled-coil region of the stalk and one in the distal motor domain, suggesting they result in altered KIF21A function. To further define the spectrum of KIF21A mutations in CFEOM we have now identified all CFEOM probands newly enrolled in our study and determined if they harbor mutations in KIF21A . Results Sixteen CFEOM1 and 29 CFEOM3 probands were studied. Three previously unreported de novo KIF21A mutations were identified in three CFEOM1 probands, all located in the same coiled-coil region of the stalk that contains all but one of the previously reported mutations. Eight additional CFEOM1 probands harbored three of the mutations previously reported in KIF21A ; seven had one of the two most common mutations, while one harbored the mutation in the distal motor domain. No mutation was detected in 5 CFEOM1 or any CFEOM3 probands. Conclusion Analysis of sixteen CFEOM1 probands revealed three novel KIF21A mutations and confirmed three reported mutations, bringing the total number of reported KIF21A mutations in CFEOM1 to 11 mutations among 70 mutation positive probands. All three new mutations alter amino acids in heptad repeats within the third coiled-coil region of the KIF21A stalk, further highlighting the importance of alterations in this domain in the etiology of CFEOM1.
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three novel mutations in KIF21A highlight the importance of the third coiled coil stalk domain in the etiology of cfeom1
BMC Genetics, 2007Co-Authors: Wai-man Chan, David G. Hunter, Caroline Andrews, Laryssa Dragan, Douglas Fredrick, Linlea Armstrong, Michael T Geraghty, Christopher J Lyons, Ahmad YazdaniAbstract:Background: Congenital fibrosis of the extraocular muscles types 1 and 3 (CFEOM1/CFEOM3) are autosomal dominant strabismus disorders that appear to result from maldevelopment of ocular nuclei and nerves. We previously reported that most individuals with CFEOM1 and rare individuals with CFEOM3 harbor heterozygous mutations in KIF21A. KIF21A encodes a kinesin motor involved in anterograde axonal transport, and the familial and de novo mutations reported to date predictably alter one of only a few KIF21A amino acids – three within the third coiled-coil region of the stalk and one in the distal motor domain, suggesting they result in altered KIF21A function. To further define the spectrum of KIF21A mutations in CFEOM we have now identified all CFEOM probands newly enrolled in our study and determined if they harbor mutations in KIF21A.
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a novel KIF21A mutation in a patient with congenital fibrosis of the extraocular muscles and marcus gunn jaw winking phenomenon
Archives of Ophthalmology, 2005Co-Authors: Koki Yamada, Caroline Andrews, David G. Hunter, Elizabeth C. EngleAbstract:Objective To determine whether congenital fibrosis of the extraocular muscles (CFEOM) with Marcus Gunn jaw-winking phenomenon (MG) can result from mutations in the KIF21A gene encoding a kinesin motor protein. Methods An individual with cfeom1 (classic autosomal dominant CFEOM) and MG underwent a comprehensive ophthalmic examination. He and his healthy parents underwent screening for mutations in the KIF21A gene by direct DNA sequencing. The clinical records of our previously described patients with CFEOM and KIF21A mutations were reviewed for evidence of more extensive dysinnervation. Results A de novo and novel KIF21A mutation 2840T→C (m947t) was present in the proband. In addition, among our previously described patients with CFEOM and KIF21A mutations, 3 individuals had MG and 1 had hypertropia during toothbrushing. Conclusions This report introduces a new cfeom1 KIF21A mutation and is, to our knowledge, the first report of a genetic defect associated with MG. The combination of cfeom1 with MG supports a primary neurogenic etiology of CFEOM resulting from KIF21A mutations. Clinical Relevance These findings will increase understanding of the etiology of CFEOM and increase awareness of the affiliation of CFEOM with MG.
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identification of KIF21A mutations as a rare cause of congenital fibrosis of the extraocular muscles type 3 cfeom3
Investigative Ophthalmology & Visual Science, 2004Co-Authors: Koki Yamada, Wai-man Chan, Caroline Andrews, Thomas M Bosley, Emin Cumhur Sener, Johan Zwaan, Paul B Mullaney, Banu T Ozturk, Nurten A Akarsu, Louise J SabolAbstract:PURPOSE. Three congenital fibrosis of the extraocular muscles phenotypes (CFEOM1-3) have been identified. Each represents a specific form of paralytic strabismus characterized by congenital restrictive ophthalmoplegia, often with accompanying ptosis. It has been demonstrated that CFEOM1 results from mutations in KIF21A and CFEOM2 from mutations in PHOX2A. This study was conducted to determine the incidence of KIF21A and PHOX2A mutations among individuals with the third CFEOM phenotype, CFEOM3. METHODS. All pedigrees and sporadic individuals with CFEOM3 in the authors' database were identified, whether the pedigrees were linked or consistent with linkage to the FEOM1, FEOM2, and/or FEOM3 loci was determined, and the appropriate pedigrees and the sporadic individuals were screened for mutations in KIF21A and PHOX2A. RESULTS. Twelve CFEOM3 pedigrees and 10 CFEOM3 sporadic individuals were identified in the database. The structures of eight of the pedigrees permitted the generation of meaningful linkage data KIF21A was screened in 17 probands, and mutations were identified in two CFEOM3 pedigrees. One pedigree harbored a novel mutation (2841G→A, M947I) and one harbored the most common and recurrent of the CFEOM1 mutations identified previously (2860C→T, R954W). None of CFEOM3 pedigrees or sporadic individuals harbored mutations in PHOX2A. CONCLUSIONS. The results demonstrate that KIF21A mutations are a rare cause of CFEOM3 and that KIF21A mutations can be nonpenetrant. Although KIF21A is the first gene to be associated with CFEOM3, the results imply that mutations in the unidentified FEOM3 gene are the more common cause of this phenotype.
Koki Yamada - One of the best experts on this subject based on the ideXlab platform.
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spatiotemporal expression pattern of KIF21A during normal embryonic development and in congenital fibrosis of the extraocular muscles type 1 cfeom1
Gene Expression Patterns, 2012Co-Authors: Jigar Desai, Koki Yamada, Marie Pia Rogines Velo, Lynne M Overman, Elizabeth C. EngleAbstract:Abstract Congenital fibrosis of the extraocular muscles type 1 (CFEOM1) is a rare inherited strabismus syndrome characterized by non-progressive ophthalmoplegia. We previously identified that CFEOM1 results from heterozygous missense mutations in KIF21A, which encodes a kinesin motor protein. Here we evaluate the expression pattern of KIF21A in human brain and muscles of control and CFEOM1 patients, and during human and mouse embryonic development. KIF21A is expressed in the cell bodies, axons, and dendrites of many neuronal populations including those in the hippocampus, cerebral cortex, cerebellum, striatum, and motor neurons of the oculomotor, trochlear, and abducens nuclei from early development into maturity, and its spatial distribution is not altered in the CFEOM1 tissues available for study. Multiple splice isoforms of KIF21A are identified in human fetal brain, but none of the reported CFEOM1 mutations are located in or near the alternatively spliced exons. KIF21A immunoreactivity is also observed in extraocular and skeletal muscle biopsies of control and CFEOM1 patients, where it co-localizes with triadin, a marker of the excitation–contractile coupling system. The diffuse and widespread expression of KIF21A in the developing human and mouse central and peripheral nervous system as well as in extraocular muscle does not account for the restricted ocular phenotype observed in CFEOM1, nor does it permit the formal exclusion of a myogenic etiology based on expression patterns alone.
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KIF21A mutations in two chinese families with congenital fibrosis of the extraocular muscles cfeom
Molecular Vision, 2010Co-Authors: Xian Yang, Elizabeth C. Engle, Caroline Andrews, Koki Yamada, Bradley J Katz, Hongzai Guan, Lifei Wang, Guiqiu Zhao, Haoyu Chen, Zongzhong TongAbstract:Purpose: Two Chinese families (XT and YT) with congenital fibrosis of the extraocular muscles (CFEOM) were identified. The purpose of this study was to determine if previously described Homo sapiens kinesin family member 21A (KIF21A) mutations were responsible for CFEOM in these two Chinese pedigrees. Methods: Clinical characterization and genetic studies were performed. Microsatellite genotyping for linkage to the CFEOM1 and CFEOM3 loci was performed. The probands were screened for KIF21A mutations by bidirectional direct sequencing. Once a mutation was detected in the proband, all other participating family members and 100 unrelated control normal individuals were screened for the mutation. Results: All affected individuals in family XT shared the common manifestations of CFEOM1. Family YT had two affected individuals, a mother and a daughter. The daughter had CFEOM1, while her mother never had congential ptosis but did have limited extraocular movements status post strabismus surgery. Haplotype analysis revealed that pedigree XT was linked to the 12q CFEOM1 locus and the affected memberes harbored the second most common missense mutation in KIF21A (2,861G>A, R954Q). Family YT harbored the most common missense de novo mutation in KIF21A (2,860C>T, R954W). Both of these mutations have been previously described. Conclusions: The observation of these two KIF21A mutations in a Chinese pedigree underscores the homogeneity of these mutations as a cause of CFEOM1 and CFEOM3 across ethnic divisions.
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a novel KIF21A mutation in a patient with congenital fibrosis of the extraocular muscles and marcus gunn jaw winking phenomenon
Archives of Ophthalmology, 2005Co-Authors: Koki Yamada, Caroline Andrews, David G. Hunter, Elizabeth C. EngleAbstract:Objective To determine whether congenital fibrosis of the extraocular muscles (CFEOM) with Marcus Gunn jaw-winking phenomenon (MG) can result from mutations in the KIF21A gene encoding a kinesin motor protein. Methods An individual with cfeom1 (classic autosomal dominant CFEOM) and MG underwent a comprehensive ophthalmic examination. He and his healthy parents underwent screening for mutations in the KIF21A gene by direct DNA sequencing. The clinical records of our previously described patients with CFEOM and KIF21A mutations were reviewed for evidence of more extensive dysinnervation. Results A de novo and novel KIF21A mutation 2840T→C (m947t) was present in the proband. In addition, among our previously described patients with CFEOM and KIF21A mutations, 3 individuals had MG and 1 had hypertropia during toothbrushing. Conclusions This report introduces a new cfeom1 KIF21A mutation and is, to our knowledge, the first report of a genetic defect associated with MG. The combination of cfeom1 with MG supports a primary neurogenic etiology of CFEOM resulting from KIF21A mutations. Clinical Relevance These findings will increase understanding of the etiology of CFEOM and increase awareness of the affiliation of CFEOM with MG.
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identification of KIF21A mutations as a rare cause of congenital fibrosis of the extraocular muscles type 3 cfeom3
Investigative Ophthalmology & Visual Science, 2004Co-Authors: Koki Yamada, Wai-man Chan, Caroline Andrews, Thomas M Bosley, Emin Cumhur Sener, Johan Zwaan, Paul B Mullaney, Banu T Ozturk, Nurten A Akarsu, Louise J SabolAbstract:PURPOSE. Three congenital fibrosis of the extraocular muscles phenotypes (CFEOM1-3) have been identified. Each represents a specific form of paralytic strabismus characterized by congenital restrictive ophthalmoplegia, often with accompanying ptosis. It has been demonstrated that CFEOM1 results from mutations in KIF21A and CFEOM2 from mutations in PHOX2A. This study was conducted to determine the incidence of KIF21A and PHOX2A mutations among individuals with the third CFEOM phenotype, CFEOM3. METHODS. All pedigrees and sporadic individuals with CFEOM3 in the authors' database were identified, whether the pedigrees were linked or consistent with linkage to the FEOM1, FEOM2, and/or FEOM3 loci was determined, and the appropriate pedigrees and the sporadic individuals were screened for mutations in KIF21A and PHOX2A. RESULTS. Twelve CFEOM3 pedigrees and 10 CFEOM3 sporadic individuals were identified in the database. The structures of eight of the pedigrees permitted the generation of meaningful linkage data KIF21A was screened in 17 probands, and mutations were identified in two CFEOM3 pedigrees. One pedigree harbored a novel mutation (2841G→A, M947I) and one harbored the most common and recurrent of the CFEOM1 mutations identified previously (2860C→T, R954W). None of CFEOM3 pedigrees or sporadic individuals harbored mutations in PHOX2A. CONCLUSIONS. The results demonstrate that KIF21A mutations are a rare cause of CFEOM3 and that KIF21A mutations can be nonpenetrant. Although KIF21A is the first gene to be associated with CFEOM3, the results imply that mutations in the unidentified FEOM3 gene are the more common cause of this phenotype.
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Heterozygous mutations of the kinesin KIF21A in congenital fibrosis of the extraocular muscles type 1 (CFEOM1)
Nature Genetics, 2003Co-Authors: Koki Yamada, Wai-man Chan, Caroline Andrews, Craig A Mckeown, Adriano Magli, Teresa De Berardinis, Anat Loewenstein, Moshe Lazar, Michael O'keefe, Robert LetsonAbstract:Congenital fibrosis of the extraocular muscles type 1 (CFEOM1; OMIM #135700) is an autosomal dominant strabismus disorder associated with defects of the oculomotor nerve. We show that individuals with CFEOM1 harbor heterozygous missense mutations in a kinesin motor protein encoded by KIF21A . We identified six different mutations in 44 of 45 probands. The primary mutational hotspots are in the stalk domain, highlighting an important new role for KIF21A and its stalk in the formation of the oculomotor axis.
R Zhang - One of the best experts on this subject based on the ideXlab platform.
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structural analyses of key features in the kank1 KIF21A complex yield mechanistic insights into the cross talk between microtubules and the cell cortex
Journal of Biological Chemistry, 2018Co-Authors: Zhuangfeng Weng, Yuan Shang, R ZhangAbstract:: The cross-talk between dynamic microtubules and the cell cortex plays important roles in cell division, polarity, and migration. A critical adaptor that links the plus ends of microtubules with the cell cortex is the KANK N-terminal motif and ankyrin repeat domains 1 (KANK1)/kinesin family member 21A (KIF21A) complex. Genetic defects in these two proteins are associated with various cancers and developmental diseases, such as congenital fibrosis of the extraocular muscles type 1. However, the molecular mechanism governing the KANK1/KIF21A interaction and the role of the conserved ankyrin (ANK) repeats in this interaction are still unclear. In this study, we present the crystal structure of the KANK1·KIF21A complex at 2.1 A resolution. The structure, together with biochemical studies, revealed that a five-helix-bundle-capping domain immediately preceding the ANK repeats of KANK1 forms a structural and functional supramodule with its ANK repeats in binding to an evolutionarily conserved peptide located in the middle of KIF21A. We also show that several missense mutations present in cancer patients are located at the interface of the KANK1·KIF21A complex and destabilize its formation. In conclusion, our study elucidates the molecular basis underlying the KANK1/KIF21A interaction and also provides possible mechanistic explanations for the diseases caused by mutations in KANK1 and KIF21A.
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Structural analyses of key features in the KANK1·KIF21A complex yield mechanistic insights into the cross-talk between microtubules and the cell cortex
Journal of Biological Chemistry, 2017Co-Authors: Zhuangfeng Weng, Yuan Shang, R ZhangAbstract:The cross-talk between dynamic microtubules and the cell cortex plays important roles in cell division, polarity, and migration. A critical adaptor that links the plus ends of microtubules with the cell cortex is the KANK N-terminal motif and ankyrin repeat domains 1 (KANK1)/kinesin family member 21A (KIF21A) complex. Genetic defects in these two proteins are associated with various cancers and developmental diseases, such as congenital fibrosis of the extraocular muscles type 1. However, the molecular mechanism governing the KANK1/KIF21A interaction and the role of the conserved ankyrin (ANK) repeats in this interaction are still unclear. In this study, we present the crystal structure of the KANK1·KIF21A complex at 2.1 A resolution. The structure, together with biochemical studies, revealed that a five-helix-bundle-capping domain immediately preceding the ANK repeats of KANK1 forms a structural and functional supramodule with its ANK repeats in binding to an evolutionarily conserved peptide located in the middle of KIF21A. We also show that several missense mutations present in cancer patients are located at the interface of the KANK1·KIF21A complex and destabilize its formation. In conclusion, our study elucidates the molecular basis underlying the KANK1/KIF21A interaction and also provides possible mechanistic explanations for the diseases caused by mutations in KANK1 and KIF21A.
Arif O. Khan - One of the best experts on this subject based on the ideXlab platform.
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Congential fibrosis of the extraocular muscles type I (CFEOM1) on the Arabian Peninsula.
Ophthalmic Genetics, 2020Co-Authors: Arif O. Khan, Dania S. Khalil, Nada Al-tassanAbstract:Purpose: To assess for KIF21A mutation in the first two reported Saudi Arabian families with the classic phenotype of congenital fibrosis of the extraocular muscles type I (CFEOM1). Methods: Clinical examination and genetic testing by amplification refractory mutation system (ARMS) assay for KIF21A R954W, the most common KIF21A mutation worldwide. Results: Clinical examination was consistent with classic CFEOM1 in both Family A and Family B. All participating patients (one child from Family A and four adults from Family B) were heterozygous for KIF21A R954W mutation. Conclusions: CFEOM1 is rare is Saudi Arabia as it is in the rest of the world. The finding of R954W mutation in the historically isolated population of the Arabian Peninsula confirms that R954 is a “hotspot” for KIF21A mutation.
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A microdeletion in the GRHL2 Gene in two unrelated patients with congenital fibrosis of the extra ocular muscles
BMC Research Notes, 2017Co-Authors: Khaled K. Abu-amero, Altaf A. Kondkar, Arif O. KhanAbstract:Congenital fibrosis of the extraocular muscles type 1 (CFEOM1) is known to be caused by mutations in KIF21A or TUBB3 or other known genes (SALL4, CHN1, HOXA1). However, affected children may harbor other genetic defects. Therefore, a candidate gene analysis (KIF21A, TUBB3 SALL4, CHN1, HOXA1) and a high-resolution array comparative genomic hybridization (arrayCGH) was performed in two unrelated children with sporadic CFEOM1. Two unrelated Saudi patients did not have any mutation(s) after sequencing the full coding regions of SALL4, CHN1, HOXA1, and TUBB3 genes; and exons 8, 20, and 21 of the KIF21A gene. However, arrayCGH revealed a 3.17 Kb deletion at chromosome 8p22 with copy number state equal to 1, indicating a heterozygous deletion. This deletion was absent in proband’s mother or father or 220 unrelated healthy individuals of similar ethnicity. The deletion encompassed only one functional gene, GRHL2, which encodes a transcription factor. In humans, defects in this gene are a cause of non-syndromic sensorineural deafness, autosomal dominant type 28 (DFNA28). We speculate that GRHL2 gene may have a role in orbital innervations and the defect in this gene (deletion) may be related to the CFEOM1 phenotype in these two children.
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The genetics of nonsyndromic bilateral Duane retraction syndrome
Journal of Aapos, 2016Co-Authors: Khaled K. Abu-amero, Arif O. Khan, Altaf A. Kondkar, Darren T. Oystreck, Thomas M BosleyAbstract:Purpose To assess the importance of monogenic mutations and chromosomal copy number variants (CNVs) in the occurrence of nonsyndromic bilateral Duane retraction syndrome (bilateral nsDRS). Methods The medical records of 12 patients with bilateral nsDRS were reviewed. Genes associated with DRS and associated congenital cranial dysinnervation disorders (SALL4, CHN1, HOXA1, TUBB3, and KIF21A) were sequenced in the standard fashion in each patient. Array comparative genomic hybridization (array CGH) was performed using Affymetrix Cytogenetics Whole-Genome 2.7M array, and the results were analyzed using Affymetrix Chromosome Analysis Suite v1.2. CNVs were assessed as unlikely to be pathologic if they were also present in the Database of Genomic Variants (DGV) or our local database of array CGH results in 150 normal individuals of Middle Eastern ethnicity. Results No patient had a sequence mutation in SALL4, CHN1, HOXA1, TUBB3, or KIF21A. These 12 patients each had 36-42 chromosomal deletions and/or duplications (mean with standard deviation, 26.25 ± 6.77), but all of these CNVs were present either in the DGV or in our local database of normal individuals of similar ethnicity and, therefore, are considered nonpathogenic. Conclusions The results reported here suggest that bilateral nsDRS is not usually associated with mutations in these genes or with chromosomal CNVs. Current evidence suggests other factors such as epigenetic and/or teratogenic abnormalities may be a potential cause of bilateral nsDRS.
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CCDD Phenotype Associated with a Small Chromosome 2 Deletion
Seminars in Ophthalmology, 2014Co-Authors: Khaled K. Abu-amero, Thomas M Bosley, Altaf A. Kondkar, Darren T. Oystreck, Arif O. KhanAbstract:AbstractPurpose: Some individuals are born with congenital limitation of ocular motility, often associated with ptosis and retraction of the globe. Many of these disorders are now known as the congenital cranial dysinnervation disorders (CCDDs). While several genes have been associated with CCDD phenotypes, there are still patients for whom the genetic basis has not been identified. Methods: Clinical evaluation and neuroimaging, sequencing of candidate genes, and array comparative genomic hybridization (array CGH). Results: The patient was a four-year-old girl with mild dysmorphism; bilateral mild ptosis; substantial limitation of abduction OS with milder limitations of abduction OD, adduction OS, and vertical gaze OS; and retraction OS > OD on attempted adduction. No mutations were detected in the HOXA1, KIF21A, SALL4, TUBB3, and CHN1 genes. Array CGH revealed a 8 Kb de novo deletion on chromosome 2 (2q24.3) that encompassed a portion of only one gene, the Xin Actin-binding Repeat containing 2 (Gene Symb...
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Nicotinic Receptor Mutation in a Mildly Dysmorphic Girl with Duane Retraction Syndrome.
Ophthalmic Genetics, 2013Co-Authors: Khaled K. Abu-amero, Arif O. Khan, Altaf A. Kondkar, Ali Hellani, Darren T. Oystreck, Thomas M BosleyAbstract:AbstractBackground: To evaluate possible monogenic and chromosomal anomalies in a patient with unilateral Duane retraction syndrome and modest dysmorphism.Materials and Methods: Clinical evaluation, sequencing of candidate genes, and array comparative genomic hybridization (array CGH).Results: The proband had unilateral Duane retraction syndrome (DRS) with low-set ears bilaterally, a high arched palate, and clinodactyly. Motor development and cognitive function were normal. Parents were first cousins, but no other family member was similarly affected. No mutations were detected in the HOXA1. KIF21A. SALL4, TUBB3, and CHN1 genes. Array CGH revealed a 16 Kb de novo deletion at chromosome 8p11.2 that encompassed a portion of only one gene, the Cholinergic Receptor, Nicotinic, Beta-3 (CHRNB3, Neuronal). This gene encodes a protein that is involved in the nicotinic acetylcholine receptor on neurons. It interacts functionally with other genes that code components of the acetylcholine receptor.Conclusions: This ...
