Recurrent Dominant Mutations Affecting Two Adjacent Residues in the Motor Domain of the Monomeric Kinesin KIF22 Result in Skeletal Dysplasia and Joint Laxity

Boyden, Eric D.; Campos-Xavier, Ana Bélinda; Kalamajski, Sebastian; Cameron, Trevor L.; Suarez, Philippe; Tanackovich, Goranka; Andria, Generoso; Ballhausen, Diana; Briggs, Michael D.; Hartley, Claire; Cohn, Daniel H.; Davidson, H. Rosemarie; Hall, Christine; Ikegawa, Shiro; Jouk, Pierre‐Simon; König, Rainer; Mégarbané, André; Nishimura, Gen; Lachman, Ralph S.; Mortier, Geert; Rimoin, David L.; Rogers, R. Curtis; Rossi, Massimiliano; Sawada, Hirotake; Scott, Richard; Unger, Sheila; Valadares, Eugênia Ribeiro; Bateman, John F.; Warman, Matthew L.; Superti‐Furga, Andrea; Bonafé, Luisa

doi:10.1016/j.ajhg.2011.10.016

Cited by 35 publications

(52 citation statements)

References 35 publications

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“…Together, our data support gain-of-function mutations underlying CFEOM1, and suggest that both homozygous and heterozygous mutant dimers can disrupt Kif21a autoinhibition. Notably, while most human mutations in other kinesins cause partial or complete loss of function, mutations in KIF22 and KIF5A highlight specific residues that could prove important for autoregulation (Boyden et al, 2011; Crimella et al, 2012). Thus, pathological alterations of autoinhibition may extend beyond KIF21A and represent a more generalized mechanism underlying disorders of kinesin function.…”

Section: Discussionmentioning

confidence: 99%

Human CFEOM1 Mutations Attenuate KIF21A Autoinhibition and Cause Oculomotor Axon Stalling

Cheng

Desai

Miranda

et al. 2014

Neuron

109

122

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SUMMARY The ocular motility disorder “Congenital fibrosis of the extraocular muscles type 1″ (CFEOM1) results from heterozygous mutations altering the motor and 3rd coiled-coil stalk of the anterograde kinesin, KIF21A. We demonstrate that Kif21a knock-in mice harboring the most common human mutation develop CFEOM. The developing axons of the oculomotor nerve’s superior division stall in the proximal nerve; the growth cones enlarge, extend excessive filopodia, and assume random trajectories. Inferior division axons reach the orbit but branch ectopically. We establish a gain-of-function mechanism and find that human motor or stalk mutations attenuate Kif21a autoinhibition, providing in vivo evidence for mammalian kinesin autoregulation. We identify Map1b as a Kif21a interacting protein and report that Map1b−/− mice develop CFEOM. The interaction between Kif21a and Map1b is likely to play a critical role in the pathogenesis of CFEOM1, and highlights a selective vulnerability of the developing oculomotor nerve to perturbations of the axon cytoskeleton.

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Section: Discussionmentioning

confidence: 99%

Human CFEOM1 Mutations Attenuate KIF21A Autoinhibition and Cause Oculomotor Axon Stalling

Cheng

Desai

Miranda

et al. 2014

Neuron

109

122

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“…Individuals with a point mutation in the motor domain of KIF22 suffer from the autosomal-dominant skeletal disorder spondyloepimetaphyseal dysplasia with joint laxity (Boyden et al, 2011; Min et al, 2011). No phenotype has been reported in Kif22 +/− mice; however, ∼50% of Kif22 − / − mouse embryos do not survive past the morula stage (Ohsugi et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Zebrafish homologs of 16p11.2, a genomic region associated with brain disorders, are active during brain development, and include two deletion dosage sensor genes

Blaker-Lee

Gupta

McCammon

et al. 2012

Disease Models &Amp; Mechanisms

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SUMMARYDeletion or duplication of one copy of the human 16p11.2 interval is tightly associated with impaired brain function, including autism spectrum disorders (ASDs), intellectual disability disorder (IDD) and other phenotypes, indicating the importance of gene dosage in this copy number variant region (CNV). The core of this CNV includes 25 genes; however, the number of genes that contribute to these phenotypes is not known. Furthermore, genes whose functional levels change with deletion or duplication (termed ‘dosage sensors’), which can associate the CNV with pathologies, have not been identified in this region. Using the zebrafish as a tool, a set of 16p11.2 homologs was identified, primarily on chromosomes 3 and 12. Use of 11 phenotypic assays, spanning the first 5 days of development, demonstrated that this set of genes is highly active, such that 21 out of the 22 homologs tested showed loss-of-function phenotypes. Most genes in this region were required for nervous system development – impacting brain morphology, eye development, axonal density or organization, and motor response. In general, human genes were able to substitute for the fish homolog, demonstrating orthology and suggesting conserved molecular pathways. In a screen for 16p11.2 genes whose function is sensitive to hemizygosity, the aldolase a (aldoaa) and kinesin family member 22 (kif22) genes were identified as giving clear phenotypes when RNA levels were reduced by ∼50%, suggesting that these genes are deletion dosage sensors. This study leads to two major findings. The first is that the 16p11.2 region comprises a highly active set of genes, which could present a large genetic target and might explain why multiple brain function, and other, phenotypes are associated with this interval. The second major finding is that there are (at least) two genes with deletion dosage sensor properties among the 16p11.2 set, and these could link this CNV to brain disorders such as ASD and IDD.

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“…Cases with SEMDJL2, leptodactylic type, exhibit spondyloepimetaphyseal dysplasia with moderate platyspondyly, metaphyseal streaks and small, fragmented epiphyses (4). Moreover, there are distinctive facial features with important midface retrusion and laryngotracheomalacia (3,4) (this publication).…”

Section: When Bone Maturation Can Be Helpful?mentioning

confidence: 97%

“…Bone age seems to be inconsistent for most of the conditions (12,28,29,34,35) except for Desbuquois dysplasia, type 1, Kim Variant, and type 2, where bone maturation is constantly advanced (5,26) and SEMDJL, leptodactylic type, where it is delayed (3,4).…”

Section: When Bone Maturation Can Be Helpful?mentioning

confidence: 99%

Chondrodysplasia with multiple dislocations: comprehensive study of a series of 30 cases

et al. 2017

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The group of chondrodysplasia with multiple dislocations includes several entities, characterized by short stature, dislocation of large joints, hand and/or vertebral anomalies. Other features, such as epiphyseal or metaphyseal changes, cleft palate, intellectual disability are also often part of the phenotype. In addition, several conditions with overlapping features are related to this group and broaden the spectrum. The majority of these disorders have been linked to pathogenic variants in genes encoding proteins implicated in the synthesis or sulfation of proteoglycans (PG). In a series of 30 patients with multiple dislocations, we have performed exome sequencing and subsequent targeted analysis of 15 genes, implicated in chondrodysplasia with multiple dislocations, and related conditions. We have identified causative pathogenic variants in 60% of patients (18/30); when a clinical diagnosis was suspected, this was molecularly confirmed in 53% of cases. Forty percent of patients remain without molecular etiology. Pathogenic variants in genes implicated in PG synthesis are of major importance in chondrodysplasia with multiple dislocations and related conditions. The combination of hand features, growth failure severity, radiological aspects of long bones and of vertebrae allowed discrimination among the different conditions. We propose key diagnostic clues to the clinician.

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Recurrent Dominant Mutations Affecting Two Adjacent Residues in the Motor Domain of the Monomeric Kinesin KIF22 Result in Skeletal Dysplasia and Joint Laxity

Cited by 35 publications

References 35 publications

Human CFEOM1 Mutations Attenuate KIF21A Autoinhibition and Cause Oculomotor Axon Stalling

Human CFEOM1 Mutations Attenuate KIF21A Autoinhibition and Cause Oculomotor Axon Stalling

Zebrafish homologs of 16p11.2, a genomic region associated with brain disorders, are active during brain development, and include two deletion dosage sensor genes

Chondrodysplasia with multiple dislocations: comprehensive study of a series of 30 cases

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