Novel fibronectin mutations and expansion of the phenotype in spondylometaphyseal dysplasia with “corner fractures”

Costantini, Alice; Valta, Helena; Baratang, Nissan Vida; Yap, Patrick; Bertola, Débora Romeo; Yamamoto, Guilherme Lopes; Kim, Chong; Chen, Jiani; Wierenga, Klaas J.; Fanning, Elizabeth A.; Escobar, Luis; McWalter, Kirsty; McLaughlin, Heather; Willaert, Rebecca; Begtrup, Amber; Alm, Jessica J.; Reinhardt, Dieter P.; Mäkitie, Outi; Campeau, Philippe M.

doi:10.1016/j.bone.2018.12.020

Cited by 17 publications

(25 citation statements)

References 51 publications

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“…For family 1, trio exome sequencing and analysis was conducted at GeneDx. 23 Assertion criteria for variant classification are available at ClinVar. For families 2 and 3, exome sequencing and analysis were performed as previously described (family 2 24 and family 3 25 ).…”

Section: Human Geneticsmentioning

confidence: 99%

Loss of Oxidation Resistance 1, OXR1, Is Associated with an Autosomal-Recessive Neurological Disease with Cerebellar Atrophy and Lysosomal Dysfunction

Wang

Rousseau

Kim

et al. 2019

The American Journal of Human Genetics

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We report an early-onset autosomal-recessive neurological disease with cerebellar atrophy and lysosomal dysfunction. We identified biallelic loss-of-function (LoF) variants in Oxidative Resistance 1 (OXR1) in five individuals from three families; these individuals presented with a history of severe global developmental delay, current intellectual disability, language delay, cerebellar atrophy, and seizures. While OXR1 is known to play a role in oxidative stress resistance, its molecular functions are not well established. OXR1 contains three conserved domains: LysM, GRAM, and TLDc. The gene encodes at least six transcripts, including some that only consist of the C-terminal TLDc domain. We utilized Drosophila to assess the phenotypes associated with loss of mustard (mtd), the fly homolog of OXR1. Strong LoF mutants exhibit late pupal lethality or pupal eclosion defects. Interestingly, although mtd encodes 26 transcripts, severe LoF and null mutations can be rescued by a single short human OXR1 cDNA that only contains the TLDc domain. Similar rescue is observed with the TLDc domain of NCOA7, another human homolog of mtd. Loss of mtd in neurons leads to massive cell loss, early death, and an accumulation of aberrant lysosomal structures, similar to what we observe in fibroblasts of affected individuals. Our data indicate that mtd and OXR1 are required for proper lysosomal function; this is consistent with observations that NCOA7 is required for lysosomal acidification.

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Section: Human Geneticsmentioning

confidence: 99%

Loss of Oxidation Resistance 1, OXR1, Is Associated with an Autosomal-Recessive Neurological Disease with Cerebellar Atrophy and Lysosomal Dysfunction

Wang

Rousseau

Kim

et al. 2019

The American Journal of Human Genetics

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“…Such observation has been reported in patients with some other osteochondrodysplasias, including spondylometaphyseal dysplasia with “corner fractures” caused by mutations in the fibronectin gene and metaphyseal anadysplasia caused by mutations in metalloproteinases. ( 48–51 ) Interestingly, incomplete penetrance and variable expression among patients with identical mutations is a common feature in ribosomopathies, ( 8 ) but the underlying mechanisms still remain largely unknown.…”

Section: Discussionmentioning

confidence: 99%

“…In family 1, we performed trio whole‐genome sequencing (WGS) as previously described. ( 21,22 ) For data analysis, we applied the following filtering criteria: (i) homozygous/compound heterozygous variant or de novo variant; (ii) MAF <0.001 the gnomAD ( 23 ) and SweGen ( 24 ) databases; and (iii) impact severity other than LOW in GEMINI. ( 25 )…”

Section: Methodsmentioning

confidence: 99%

Novel RPL13 Variants and Variable Clinical Expressivity in a Human Ribosomopathy With Spondyloepimetaphyseal Dysplasia

Costantini

Alm

Tonelli

et al. 2020

Journal of Bone and Mineral Research

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Spondyloepimetaphyseal dysplasias (SEMDs) are a heterogeneous group of disorders with variable growth failure and skeletal impairments affecting the spine and long bone epiphyses and metaphyses. Here we report on four unrelated families with SEMD in which we identified two monoallelic missense variants and one monoallelic splice site variant in RPL13, encoding the ribosomal protein eL13. In two out of four families, we observed autosomal dominant inheritance with incomplete penetrance and variable clinical expressivity; the phenotypes of the mutation‐positive subjects ranged from normal height with or without hip dysplasia to severe SEMD with severe short stature and marked skeletal dysplasia. In vitro studies on patient‐derived dermal fibroblasts harboring RPL13 missense mutations demonstrated normal eL13 expression, with proper subcellular localization but reduced colocalization with eL28 (p < 0.001). Cellular functional defects in fibroblasts from mutation‐positive subjects indicated a significant increase in the ratio of 60S subunits to 80S ribosomes (p = 0.007) and attenuated global translation (p = 0.017). In line with the human phenotype, our rpl13 mutant zebrafish model, generated by CRISPR‐Cas9 editing, showed cartilage deformities at embryonic and juvenile stages. These findings extend the genetic spectrum of RPL13 mutations causing this novel human ribosomopathy with variable skeletal features. Our study underscores for the first time incomplete penetrance and broad phenotypic variability in SEMD‐RPL13 type and confirms impaired ribosomal function. Furthermore, the newly generated rpl13 mutant zebrafish model corroborates the role of eL13 in skeletogenesis. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)..

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“…SMD-CF was first described by Sutcliffe in 1966 and it was recognized as a separate entity in 1990 ( 19 ). Since then, approximately 30 families have been reported and while pathogenic variants in COL2A1 were identified in some subjects with SMD-CF, most of the patients lacked a genetic diagnosis for several decades ( 17 , 20 , 21 ). Nowadays, 11 different disease-causing missense variants and a single amino acid deletion in FN1 have been reported in 13 families with SMD-CF ( 17 , 20 , 21 ).…”

Section: Defects In Fibronectin-1 Cause Smd-corner Fracture Typementioning

confidence: 99%

“…Since then, approximately 30 families have been reported and while pathogenic variants in COL2A1 were identified in some subjects with SMD-CF, most of the patients lacked a genetic diagnosis for several decades ( 17 , 20 , 21 ). Nowadays, 11 different disease-causing missense variants and a single amino acid deletion in FN1 have been reported in 13 families with SMD-CF ( 17 , 20 , 21 ). In addition to corner fractures, patients typically feature short stature, developmental coxa vara, scoliosis, and abnormal ossification at the growth plate and secondary ossification sites.…”

Section: Defects In Fibronectin-1 Cause Smd-corner Fracture Typementioning

confidence: 99%

New gene discoveries in skeletal diseases with short stature

Costantini

Muurinen

Mäkitie

2021

Endocrine Connections

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In the last decade, the widespread use of massively-parallel sequencing has considerably boosted the number of novel gene discoveries in monogenic skeletal diseases with short stature. Defects in genes playing a role in the maintenance and function of the growth plate, the site of longitudinal bone growth, are a well-known cause of skeletal diseases with short stature. However, several genes involved in extracellular matrix composition or maintenance as well as genes partaking in various biological processes have also been characterized. This review aims to describe the latest genetic findings in spondyloepiphyseal and spondyloepimetaphyseal dysplasias and in some monogenic forms of isolated short stature. Strategies on how to successfully characterize novel skeletal phenotypes with short stature and genetic approaches to detect and validate novel gene-disease correlations will be discussed in detail. Finally, novel genetic mechanisms in the field of skeletal diseases, including variants affecting miRNAs and disrupting the chromatin structure, will be described. In summary, we discuss the latest gene discoveries underlying skeletal diseases with short stature and emphasize the importance of characterizing novel molecular mechanisms for genetic counseling, optimal management of the disease and for therapeutic innovations.

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Novel fibronectin mutations and expansion of the phenotype in spondylometaphyseal dysplasia with “corner fractures”

Cited by 17 publications

References 51 publications

Loss of Oxidation Resistance 1, OXR1, Is Associated with an Autosomal-Recessive Neurological Disease with Cerebellar Atrophy and Lysosomal Dysfunction

Loss of Oxidation Resistance 1, OXR1, Is Associated with an Autosomal-Recessive Neurological Disease with Cerebellar Atrophy and Lysosomal Dysfunction

Novel RPL13 Variants and Variable Clinical Expressivity in a Human Ribosomopathy With Spondyloepimetaphyseal Dysplasia

New gene discoveries in skeletal diseases with short stature

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