Seven patients with Smith-McCort dysplasia 2: Four novel nonsense variants in RAB33B and follow-up findings

Tüysüz, Beyhan; Geyik, Filiz; Yıldırım, Timur; Alkaya, Dilek Uludağ; Sharifova, Sabine; Kafadar, Ali

doi:10.1016/j.ejmg.2021.104248

Cited by 3 publications

(8 citation statements)

References 23 publications

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“…These data, together with the slight increase in ultimate load and ultimate stress, suggest that intrinsically, Rab33b mutant bones may be stronger compared to WT bones. Interestingly, among all the typical features that SMC2 patients may present (Alshammari et al, 2012;Dupuis et al, 2013;Tuysuz et al, 2021), skeletal fractures are not one of them which supports our finding. Finally, changes in protein glycosylation have also been Histology and immunofluorescence staining.…”

Section: Figuresupporting

confidence: 90%

“…It is also interesting to note that, while the effects of the Rab33b variant were subtle, they were only detected in male (both heterozygous and homozygous) and not female mice. While we don't have a current explanation for this sex difference, a total of fifteen SMC2 patients (9 females) have currently been described in the literature and we found no reference that the disease presents earlier and/or with more severity in males versus females (Alshammari et al, 2012;Dupuis et al, 2013;Salian et al, 2017;Tuysuz et al, 2021). This aspect may require further attention by clinicians.…”

Section: Figurementioning

confidence: 73%

“…(Kaufman et al, 1971;Beighton, 1990;Nakamura et al, 1997;Neumann et al, 2006). Skeletal defects present after birth, usually between 18 and 48 months of age, and are progressive resulting in significant deformities (Tuysuz et al, 2021). Typical features of the disease are short trunk dwarfism with barrel-shaped chest, short neck, double-humped vertebral bodies, platyspondyly, and lacy iliac crests, which can be accompanied by additional defects such as genu valgum, brachydactyly, joint contractures and others (Tuysuz et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

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Insights in Genetics of Common and Rare Diseases: 2022

2024

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Frontiers is more than just an open access publisher of scholarly articles: it is a pioneering approach to the world of academia, radically improving the way scholarly research is managed. The grand vision of Frontiers is a world where all people have an equal opportunity to seek, share and generate knowledge. Frontiers provides immediate and permanent online open access to all its publications, but this alone is not enough to realize our grand goals. Frontiers journal seriesThe Frontiers journal series is a multi-tier and interdisciplinary set of openaccess, online journals, promising a paradigm shift from the current review, selection and dissemination processes in academic publishing. All Frontiers journals are driven by researchers for researchers; therefore, they constitute a service to the scholarly community. At the same time, the Frontiers journal series operates on a revolutionary invention, the tiered publishing system, initially addressing specific communities of scholars, and gradually climbing up to broader public understanding, thus serving the interests of the lay society, too. Dedication to qualityEach Frontiers article is a landmark of the highest quality, thanks to genuinely collaborative interactions between authors and review editors, who include some of the world's best academicians. Research must be certified by peers before entering a stream of knowledge that may eventually reach the public -and shape society; therefore, Frontiers only applies the most rigorous and unbiased reviews. Frontiers revolutionizes research publishing by freely delivering the most outstanding research, evaluated with no bias from both the academic and social point of view. By applying the most advanced information technologies, Frontiers is catapulting scholarly publishing into a new generation. What are Frontiers Research Topics?Frontiers Research Topics are very popular trademarks of the Frontiers journals series: they are collections of at least ten articles, all centered on a particular subject. With their unique mix of varied contributions from Original Research to Review Articles, Frontiers Research Topics unify the most influential researchers, the latest key findings and historical advances in a hot research area.

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Section: Figuresupporting

confidence: 90%

Section: Figurementioning

confidence: 73%

Section: Discussionmentioning

confidence: 99%

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Insights in Genetics of Common and Rare Diseases: 2022

2024

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“…Early orthopaedic intervention and management is known to improve some of these deformities 34. The majority of patients described thus far have been children and long-term outcomes are available only in a few adults 25 35…”

Section: Discussionmentioning

confidence: 99%

Clinical, radiological and molecular studies in 24 individuals with Dyggve-Melchior-Clausen dysplasia and Smith-McCort dysplasia from India

et al. 2022

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BackgroundDyggve-Melchior-Clausen dysplasia (DMC) and Smith-McCort dysplasia (SMC types 1 and 2) are rare spondyloepimetaphyseal dysplasias with identical radiological findings. The presence of intellectual disability in DMC and normal intellect in SMC differentiates the two. DMC and SMC1 are allelic and caused by homozygous or compound heterozygous variants in DYM. SMC2 is caused by variations in RAB33B. Both DYM and RAB33B are important in intravesicular transport and function in the Golgi apparatus.MethodsDetailed clinical phenotyping and skeletal radiography followed by molecular testing were performed in all affected individuals. Next-generation sequencing and Sanger sequencing were used to confirm DYM and RAB33B variants. Sanger sequencing of familial variants was done in all parents.Results24 affected individuals from seven centres are described. 18 had DMC and 6 had SMC2. Parental consanguinity was present in 15 of 19 (79%). Height <3 SD and gait abnormalities were seen in 20 and 14 individuals, respectively. The characteristic radiological findings of lacy iliac crests and double-humped vertebral bodies were seen in 96% and 88% of the affected. Radiological findings became attenuated with age. 23 individuals harboured biallelic variants in either DYM or RAB33B. Fourteen different variants were identified, out of which 10 were novel. The most frequently occurring variants in this group were c.719 C>A (3), c.1488_1489del (2), c.1484dup (2) and c.1563+2T>C (2) in DYM and c.400C>T (2) and c.186del (2) in RAB33B. The majority of these have not been reported previously.ConclusionThis large cohort from India contributes to the increasing knowledge of clinical and molecular findings in these rare ‘Golgipathies’.

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“…Smith-McCort (SMC) dysplasia and Dyggve-Melchior-Clausen (DMC) dysplasia are similar, rare, autosomal recessive, osteochondrodysplasias that share identical radiologic features and cartilage histology ( Kaufman et al, 1971 ; Beighton, 1990 ; Nakamura et al, 1997 ; Neumann et al, 2006 ). Skeletal defects present after birth, usually between 18 and 48 months of age, and are progressive resulting in significant deformities ( Tuysuz et al, 2021 ). Typical features of the disease are short trunk dwarfism with barrel-shaped chest, short neck, double-humped vertebral bodies, platyspondyly, and lacy iliac crests, which can be accompanied by additional defects such as genu valgum, brachydactyly, joint contractures and others ( Tuysuz et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

A Rab33b missense mouse model for Smith-McCort dysplasia shows bone resorption defects and altered protein glycosylation

et al. 2023

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Smith McCort (SMC) dysplasia is a rare, autosomal recessive, osteochondrodysplasia that can be caused by pathogenic variants in either RAB33B or DYM genes. These genes codes for proteins that are located at the Golgi apparatus and have a role in intracellular vesicle trafficking. We generated mice that carry a Rab33b disease-causing variant, c.136A>C (p.Lys46Gln), which is identical to that of members from a consanguineous family diagnosed with SMC. In male mice at 4 months of age, the Rab33b variant caused a mild increase in trabecular bone thickness in the spine and femur and in femoral mid-shaft cortical thickness with a concomitant reduction of the femoral medullary area, suggesting a bone resorption defect. In spite of the increase in trabecular and cortical thickness, bone histomorphometry showed a 4-fold increase in osteoclast parameters in homozygous Rab33b mice suggesting a putative impairment in osteoclast function, while dynamic parameters of bone formation were similar in mutant versus control mice. Femur biomechanical tests showed an increased in yield load and a progressive elevation, from WT to heterozygote to homozygous mutants, of bone intrinsic properties. These findings suggest an overall impact on bone material properties which may be caused by disturbed protein glycosylation in cells contributing to skeletal formation, supported by the altered and variable pattern of lectin staining in murine and human tissue cultured cells and in liver and bone murine tissues. The mouse model only reproduced some of the features of the human disease and was sex-specific, manifesting in male but not female mice. Our data reveal a potential novel role of RAB33B in osteoclast function and protein glycosylation and their dysregulation in SMC and lay the foundation for future studies.

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Seven patients with Smith-McCort dysplasia 2: Four novel nonsense variants in RAB33B and follow-up findings

Cited by 3 publications

References 23 publications

Insights in Genetics of Common and Rare Diseases: 2022

Insights in Genetics of Common and Rare Diseases: 2022

Clinical, radiological and molecular studies in 24 individuals with Dyggve-Melchior-Clausen dysplasia and Smith-McCort dysplasia from India

A Rab33b missense mouse model for Smith-McCort dysplasia shows bone resorption defects and altered protein glycosylation

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