Functional variants of POC5 identified in patients with idiopathic scoliosis

Patten, Scott B.; Margaritte‐Jeannin, Patricia; Bernard, J.; Alix, Eudéline; Labalme, Audrey; Besson, Alicia; Girard, Simon L.; Fendri, K.; Fraisse, Nicolas; Biot, B.; Poizat, C.; Campan-Fournier, Amandine; Abelin-Genevois, Kariman; Cunin, Vincent; Zaouter, Charlotte; Liao, Meijiang; Lamy, Raphaelle; Lesca, Gaëtan; Menassa, Rita; Marcaillou, Charles; Letexier, Mélanie; Sanlaville, Damien; Bérard, J; Rouleau, Guy A.; Clerget‐Darpoux, Françoise; Drapeau, Pierre; Moldovan, Florina; Edery, Patrick

doi:10.1172/jci77262

Cited by 93 publications

(87 citation statements)

References 18 publications

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“…10% of AIS have a familial disease transmitted by Mendelian inheritance, and the causes of the remaining 90% sporadic patients are multifactorial (Cheng, Tang, Yeung, & Miller, 2007;Riseborough & Wynne-Davies, 1973;Wynne-Davies, 1968). In our study, we found that the MAPK7 c.886A> G variant was cosegregated with the phenotype in some pedigrees with AD form inheritance of scoliosis, and also in general population was associated with the susceptibility of AIS, suggesting that Recent genetic studies have conducted faithful scoliosis models using zebrafish (Grimes et al, 2016;Kou et al, 2013;Patten et al, 2015), providing a functional means to validate human AIS-associated genetic variants, as well as to examine the biological causes of scoliosis. To establish a clear link between MAPK7 and AIS, we silenced the mapk7 gene by means of the CRISPR/Cas9-mediated genome editing system and successfully recapitulated the characteristic phenotype of idiopathic scoliosis in the mutant adult zebrafish.…”

Section: Discussionsupporting

confidence: 53%

“…1A) of the 21 Chinese AD-AIS families but only in 3.6% (N = 41, 40 heterozygotes and one homozygote) of the 1,124 Chinese simplex patients (86 simplex patients in the discovery cohort and 1,038 simplex patients in the replication cohort). This, taken together with the similarly low detection rates of the functional POC5 variants in the European AD-AIS families and simplex patients(Patten et al, 2015), suggests that further efforts are required to resolve the complex genetic architecture underlying AIS. The biological cause underlying how MAPK7 causes AIS thus remains unknown.…”

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confidence: 99%

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Rare coding variants in MAPK7 predispose to adolescent idiopathic scoliosis

et al. 2017

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Adolescent idiopathic scoliosis (AIS) is a complex genetic disorder characterized by three-dimensional spinal curvatures, affecting 2%-3% of school age children, yet the causes underlying AIS are not well understood. Here, we first conducted a whole-exome sequencing and linkage analysis on a three-generation Chinese family with autosomal-dominant (AD) AIS, and then performed targeted sequencing in a discovery cohort comprising 20 AD AIS families and 86 simplex patients, and finally identified three disease-associated missense variants (c.886G> A, c.1943C> T, and c.1760C> T) in the MAPK7 gene (encoding mitogen-activated protein kinase 7). Genotyping of the three rare variants in a Chinese replication cohort comprising 1,038 simplex patients and 1,841 controls showed that their combined allele frequency was significantly over-represented in patients as compared with controls (2.0% [41/2,076] vs. 0.7% [27/3,682]; odds ratio = 2.7; P = 2.8 × 10 ). In vitro, we demonstrated that the three MAPK7 mutants disrupted nuclear translocation in cellular models, which is necessary for the normal function of MAPK7. In vivo, we also conducted CRISPR/Cas9-mediated deletion of mapk7 in zebrafish recapitulating the characteristic phenotype of idiopathic scoliosis. Taken together, our findings suggest that rare coding variants in MAPK7 predispose to AIS, providing clues to understanding the mechanisms of AIS.

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Section: Discussionsupporting

confidence: 53%

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confidence: 99%

Rare coding variants in MAPK7 predispose to adolescent idiopathic scoliosis

et al. 2017

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“…It is recruited to the procentrioles in G 2 phase (Fig. 1C), where it plays a crucial role in initiation of the procentriole elongation (59), and it has been shown that mutations in this gene are associated with idiopathic scoliosis (64). The location of its function in the centriole duplication pathway therefore sits downstream of the PLK4 and SAS6 module.…”

Section: Centrin and Centrin-binding Proteins At Human Centrosomesmentioning

confidence: 99%

Duplication of the Yeast Spindle Pole Body Once per Cell Cycle

Rüthnick

Schiebel

2016

Molecular and Cellular Biology

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bThe yeast spindle pole body (SPB) is the functional equivalent of the mammalian centrosome. Centrosomes and SPBs duplicate exactly once per cell cycle by mechanisms that use the mother structure as a platform for the assembly of the daughter. The conserved Sfi1 and centrin proteins are essential components of the SPB duplication process. Sfi1 is an elongated molecule that has, in its center, 20 to 23 binding sites for the Ca 2؉ -binding protein centrin. In the yeast Saccharomyces cerevisiae, all Sfi1 N termini are in contact with the mother SPB whereas the free C termini are distal to it. During S phase and early mitosis, cyclin-dependent kinase 1 (Cdk1) phosphorylation of mainly serine residues in the Sfi1 C termini blocks the initiation of SPB duplication ("off" state). Upon anaphase onset, the phosphatase Cdc14 dephosphorylates Sfi1 ("on" state) to promote antiparallel and shifted incorporation of cytoplasmic Sfi1 molecules into the half-bridge layer, which thereby elongates into the bridge. The Sfi1 C termini of the two Sfi1 layers localize in the bridge center, whereas the N termini of the newly assembled Sfi1 molecules are distal to the mother SPB. These free Sfi1 N termini then assemble the new SPB in G 1 phase. Recruitment of Sfi1 molecules into the anaphase SPB and bridge formation were also observed in Schizosaccharomyces pombe, suggesting that the Sfi1 bridge cycle is conserved between the two organisms. Thus, restricting SPB duplication to one event per cell cycle requires only an oscillation between Cdk1 kinase and Cdc14 phosphatase activities. This clockwork regulates the "on"/"off" state of the Sfi1-centrin receiver.T he mammalian centrosome and the yeast spindle pole body (SPB) are both able to nucleate microtubules (MTs) from tubulin subunits and are therefore collectively named MT organizing centers (MTOCs). A second common feature is the duplication of the centrosome and SPB just once during each cell division cycle. In each case, it is the mother centrosome or SPB that provides the platform for the assembly of the daughter (1-3).In yeast, the SPB is absolutely critical for mitotic spindle formation and chromosome segregation. This is because alternative MT assembly pathways, such as the RCC1/Ran-GTP-or augmindependent MT nucleation pathways, are absent from yeast (4, 5). In contrast, human cells can assemble a mitotic spindle even in the absence of centrosomes because of centrosome-independent MT formation and the presence of spindle assembly pathways. Recent studies have shown that the ability of human cells to tolerate loss of centrosomes or centrosome overduplication is reliant upon the inactivation of the p53 tumor suppressor gene that otherwise arrests these abnormal cells in G 1 phase (6, 7). How cells sense centrosome number defects is currently not understood. Yet it is becoming clearer why such a surveillance mechanism is important. Centrosome overamplification may contribute to cell transformation or enhance the aggressive nature of already transformed cells (8, 9). It is therefore...

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“…If the child with Ectopia Lentis is the only one in the family and parents are related (consanguineous), this is most likely an autosomal recessive type of Ectopia Lentis due to ADAMTSL4, ADAMTS18, or other gene [ 5 ]. Adolescent idiopathic scoliosis can also be inherited dominantly, and is now being shown to be due to separate genes [ 7 ].…”

Section: Physical Examinationmentioning

confidence: 99%

Diagnosis and Management (Summary)

Child

2016

Diagnosis and Management of Marfan Syndrome

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Functional variants of POC5 identified in patients with idiopathic scoliosis

Cited by 93 publications

References 18 publications

Rare coding variants in MAPK7 predispose to adolescent idiopathic scoliosis

Rare coding variants in MAPK7 predispose to adolescent idiopathic scoliosis

Duplication of the Yeast Spindle Pole Body Once per Cell Cycle

Diagnosis and Management (Summary)

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