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

Boyden, Ed; Campos-Xavier, AB; Kalamajski, Sebastian; Cameron, TL; Suarez, Philippe; Tanačković, Goranka; Andria, Generoso; Ballhausen, Diana; Briggs,; Hartley, Claire; Dh, Cohn; Davidson, H. Rosemarie; Hall, C.N.; Ikegawa, Shinichi; Jouk, Pierre‐Simon; König, Rainer; Mégarbané, André; Nishimura, Gen; Lachman, RS; Dl, Rimoin; Rc, Rogers; Rossi, Marcello; Sawada, Hirotake; Scott, Rod; Unger, Sheila; Valadares, ER; Bateman, John F.; Warman, ML; Superti‐Furga, Andrea; Bonafé, Luisa

doi:10.1016/j.ajhg.2011.12.012

Cited by 4 publications

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“…KIF22 variants are associated with retarded bone age, as well as very slender metacarpals/metatarsals (3,4) (this publication). Cases with SEMDJL2, leptodactylic type, exhibit spondyloepimetaphyseal dysplasia with moderate platyspondyly, metaphyseal streaks and small, fragmented epiphyses (4).…”

Section: Discussionmentioning

confidence: 94%

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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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Section: Discussionmentioning

confidence: 94%

“…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: Discussionmentioning

confidence: 99%

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

et al. 2017

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“…16 Tethering and fusion of exocytic vesicles are required for ciliogenesis, which is important for skeletal development. 17 A postulated role of KIF22 in cartilage biology by implication in intracellular transport and/or cilia-associated transport mechanisms 3,4 indicates a possible link between kinesins (eg KIF22) and the exocyst complex (eg EXOC6B). In line with this, NIN, another gene associated with an SEMD-JL2-like phenotype, 8 encodes ninein required for centrosome maturation and architecture.…”

Section: Resultsmentioning

confidence: 99%

“…2 Missense variants affecting one of two amino acids in the motor domain of the kinesin family member KIF22 have been identified to cause SEMD-JL2. 3,4 Key features of SEMD with joint laxity, type 1, with or without fractures (SEMD-JL1; MIM 271640), which is caused by biallelic variants in B3GALT6, 5,6 are joint laxity and dislocations and SEMD. Affected individuals show facial dysmorphism, kyphoscoliosis at birth, talipes equinovarus, cleft palate and congenital heart disease.…”

Section: Introductionmentioning

confidence: 99%

A novel multiple joint dislocation syndrome associated with a homozygous nonsense variant in the EXOC6B gene

et al. 2015

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We report two brothers from a consanguineous couple with spondyloepimetaphyseal dysplasia (SEMD), multiple joint dislocations at birth, severe joint laxity, scoliosis, gracile metacarpals and metatarsals, delayed bone age and poorly ossified carpal and tarsal bones, probably representing a yet uncharacterized SEMD with laxity and dislocations. This condition has clinical overlap with autosomal dominantly inherited SEMD with joint laxity, leptodactylic type caused by recurrent missense variants in the kinesin family member 22 gene (KIF22). Single-nucleotide polymorphism array analysis and whole-exome sequencing in the two affected siblings revealed a shared homozygous nonsense variant [c.906T4A/p.(Tyr302*)] in EXOC6B as the most likely cause. EXOC6B encodes a component of the exocyst complex required for tethering secretory vesicles to the plasma membrane. As transport of vesicles from the golgi apparatus to the plasma membrane occurs through kinesin motor proteins along microtubule tracks, the function of EXOC6B is linked to KIF22 suggesting a common pathogenic mechanism in skeletal dysplasias with joint laxity and dislocations. INTRODUCTIONSkeletal dysplasias with multiple joint dislocations is a heterogeneous group of disorders comprising~10 distinct entities. 1 Spondyloepimetaphyseal dysplasia (SEMD) with joint laxity type 2 (leptodactylic type, Hall type or SEMD-JL2; MIM 603546) is an autosomal dominant skeletal dysplasia with short stature, multiple joint dislocations and/or laxity, delayed ossification of carpals, small carpus, severe epiphyseal and mild metaphyseal changes, mild vertebral body deformities and gracile metacarpals. 2 Missense variants affecting one of two amino acids in the motor domain of the kinesin family member KIF22 have been identified to cause SEMD-JL2. 3,4 Key features of SEMD with joint laxity, type 1, with or without fractures (SEMD-JL1; MIM 271640), which is caused by biallelic variants in B3GALT6, 5,6 are joint laxity and dislocations and SEMD. Affected individuals show facial dysmorphism, kyphoscoliosis at birth, talipes equinovarus, cleft palate and congenital heart disease. 7 Another SEMD-JL2-like phenotype is associated with a homozygous missense variant in NIN. 8 Here, we report two brothers with a new type of autosomal recessive SEMD with laxity and joint dislocations. We used single-nucleotide polymorphism (SNP) array analysis and whole-exome sequencing (WES) to identify a homozygous nonsense variant in EXOC6B in the affected siblings.

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“…Type 1 (SEMDJL1; OMIM 271640), which has an autosomal recessive inheritance, is caused by homozygous or compound heterozygous mutations in the B3GALT6 gene (OMIM 615291) in chromosome 1p36 [Malfait et al, 2013;Nakajima et al, 2013], and type 2 (SEMDJL2; OMIM 603546), with autosomal dominant inheritance, is caused by heterozygous mutations in the KIF22 gene (OMIM 603213) in chromosome 16p11 [Boyden et al, 2011;Min et al, 2011].…”

Section: Spondyloepimetaphysialmentioning

confidence: 99%

Spondyloepimetaphysial Dysplasia with Joint Laxity in Three Siblings with B3GALT6 Mutations

et al. 2017

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Spondyloepimetaphyseal dysplasia with joint laxity type 1 (SEMDJL1) is a rare entity with a recessive inheritance. In this report, we describe 3 affected members of the same family who present with short stature, hyperlaxity with secondary spinal malalignment, ulnar subluxation, developmental dysplasia of the hips, and craniofacial alterations; one member also had learning difficulties. DNA analysis showed compound heterozygous variants in the B3GALT6 gene (c.901_921dup, c.511C>T) in all 3 patients, inherited from the parents. This family demonstrates the clinical variability of SEMDJL1.

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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 4 publications

References 0 publications

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

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

A novel multiple joint dislocation syndrome associated with a homozygous nonsense variant in the EXOC6B gene

Spondyloepimetaphysial Dysplasia with Joint Laxity in Three Siblings with B3GALT6 Mutations

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