Variants affecting diverse domains of MEPE are associated with two distinct bone disorders, a craniofacial bone defect and otosclerosis

Schrauwen, Isabelle; Valgaeren, Hanne; Tomás‐Roca, Laura; Sommen, Manou; Altunoğlu, Umut; Wesdorp, Mieke; Beyens, Matthias; Fransen, Erik; Nasır, Abdul; Vandeweyer, Geert; Schepers, Anne; Rahmoun, Mohammed Nadjib; Beusekom, Ellen van; Huentelman, Matt; Offeciers, Erwin; Dhooghe, Ingeborg; Huber, Alexander; Heyning, Paul Van de; Zanetti, Diego; Leenheer, Els De; Gilissen, Christian; Hoischen, Alexander; Cremers, C.W.R.J.; Verbist, Berit M.; Brouwer, Arjan P.M. de; Padberg, George W.; Pennings, Ronald J.E.; Kayserili, Hülya; Kremer, Hannie; Camp, Guy Van; Bokhoven, Hans van

doi:10.1038/s41436-018-0300-5

Cited by 19 publications

(18 citation statements)

References 39 publications

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“…To date, two genome wide association studies (GWAS) have been performed, showing strong association signals in RELN,11q13.1, TGFB1, MEPE and genes involved in bone remodeling (Rämö et al 2020;Schrauwen et al 2009). Next-generation sequencing (NGS) in otosclerosis research has led to succesful identification of pathogenic variants in MEPE (Schrauwen et al 2019) and SERPINF1 (Ziff et al 2016), although the pathogenic role of the latter is under debate (Valgaeren et al 2019).…”

Section: Introductionmentioning

confidence: 99%

A wide range of protective and predisposing variants in aggrecan influence the susceptibility for otosclerosis

et al. 2021

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In this study we investigated the association of ACAN variants with otosclerosis, a frequent cause of hearing loss among young adults.We sequenced the coding, 5'-UTR and 3'-UTR regions of ACAN in 1497 unrelated otosclerosis cases and 1437 matched controls from six different subpopulations. The association between variants in ACAN and the disease risk was tested through single variant and gene-based association tests.After correction for multiple testing, 14 variants were significantly associated with otosclerosis, ten of which represented independent association signals. Eight variants showed a consistent association across all subpopulations. Allelic odds ratios of the variants identified four predisposing and ten protective variants. Gene-based tests showed association of very rare variants in the 3'-UTR with the phenotype.The associated exonic variants are all located in the CS domain of ACAN and include both protective and predisposing variants with a broad spectrum of effect sizes and population frequencies. This includes variants with a strong effect size and low frequency, typical for monogenic diseases, to low effect size variants with high frequency, characteristic for common complex traits. This single-gene allelic spectrum with both protective and predisposing alleles is unique in the field of complex 4 diseases. In conclusion, these findings are a significant advancement to the understanding of the etiology of otosclerosis.

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Section: Introductionmentioning

confidence: 99%

A wide range of protective and predisposing variants in aggrecan influence the susceptibility for otosclerosis

et al. 2021

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“…Recently, Shrauwen and colleagues proposed a model of otosclerosis in which increased bone turnover results from mutations ablating two functional motifs of MEPE , leading to both accelerated osteoclast differentiation and enhanced mineralization and thus increased bone turnover. 38 In contrast with otosclerosis, they observed frameshift mutations ablating only one functional motif of MEPE in individuals with a severe craniofacial defect with thickening of the skull, potentially reflecting an unopposed increase in mineralization. Here, we replicate at genome-wide significance an association between otosclerosis and a frameshift mutation that is likely to ablate both functional motifs in MEPE .…”

Section: Discussionmentioning

confidence: 98%

Genome-wide Screen of Otosclerosis in Population Biobanks: 18 Loci and Shared Heritability with Skeletal Structure

Kiiskinen

Karjalainen

et al. 2020

Preprint

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Otosclerosis is one of the most common causes of conductive hearing loss, affecting 0.3% of the population. It typically presents in adulthood and half of the patients have a positive family history. The pathophysiology of otosclerosis is poorly understood and treatment options are limited. A previous genome-wide association study (GWAS) identified a single association locus in an intronic region of RELN. Here, we report a meta-analysis of GWAS studies of otosclerosis in three population-based biobanks comprising 2,413 cases and 762,382 controls. We identify 15 novel risk loci (p < 5*10−8) and replicate the regions of RELN and two previously reported candidate genes (TGFB1 and MEPE). Implicated genes in many loci are essential for bone remodelling or mineralization. Otosclerosis is genetically correlated with height and fracture risk, and the association loci overlap with severe skeletal disorders. Our results highlight TGFβ1 signalling for follow-up mechanistic studies.

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“…RGD domain variants causing its degradation or lower expression are associated with hereditary congenital facial paresis, a disorder with uni- or bilateral VII cranial nerve maldevelopment, probably due to a nerve disruption for the diploic thickening of the bony facial canal. Alternatively, variants resulting in RGD and ASARM-truncated protein are associated with adult otosclerosis (MIM 166800), featured by hypoacusia caused by abnormal bone remodeling of the otic capsule [ 66 ]. To date, these phenotypes have not been reported in RS, suggesting that hypophosphorylation due to FAM20C deficiency could be partially compensated by other phosphorylation enzymes or functional pathways.…”

Section: Fam20c Biological Function In Bone: Sibling Proteinsmentioning

confidence: 99%

FAM20C Overview: Classic and Novel Targets, Pathogenic Variants and Raine Syndrome Phenotypes

Palma‐Lara

Pérez-Ramírez

Alonso-Themann

et al. 2021

IJMS

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FAM20C is a gene coding for a protein kinase that targets S-X-E/pS motifs on different phosphoproteins belonging to diverse tissues. Pathogenic variants of FAM20C are responsible for Raine syndrome (RS), initially described as a lethal and congenital osteosclerotic dysplasia characterized by generalized atherosclerosis with periosteal bone formation, characteristic facial dysmorphisms and intracerebral calcifications. The aim of this review is to give an overview of targets and variants of FAM20C as well as RS aspects. We performed a wide phenotypic review focusing on clinical aspects and differences between all lethal (LRS) and non-lethal (NLRS) reported cases, besides the FAM20C pathogenic variant description for each. As new targets of FAM20C kinase have been identified, we reviewed FAM20C targets and their functions in bone and other tissues, with emphasis on novel targets not previously considered. We found the classic lethal and milder non-lethal phenotypes. The milder phenotype is defined by a large spectrum ranging from osteonecrosis to osteosclerosis with additional congenital defects or intellectual disability in some cases. We discuss our current understanding of FAM20C deficiency, its mechanism in RS through classic FAM20C targets in bone tissue and its potential biological relevance through novel targets in non-bone tissues.

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Variants affecting diverse domains of MEPE are associated with two distinct bone disorders, a craniofacial bone defect and otosclerosis

Cited by 19 publications

References 39 publications

A wide range of protective and predisposing variants in aggrecan influence the susceptibility for otosclerosis

A wide range of protective and predisposing variants in aggrecan influence the susceptibility for otosclerosis

Genome-wide Screen of Otosclerosis in Population Biobanks: 18 Loci and Shared Heritability with Skeletal Structure

FAM20C Overview: Classic and Novel Targets, Pathogenic Variants and Raine Syndrome Phenotypes

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