Intermediate autosomal recessive osteopetrosis with a large noncoding deletion in <i>SNX10</i>: A case report

Baer, Sarah; Schaefer, Eric; Michot, Caroline; Fischbach, Michel; Morelle, Guillaume; Ben‐David, Miriam Friedman; Castelle, Martin; Moshous, Despina; Collet, Corinne

doi:10.1002/pbc.27751

Cited by 7 publications

(4 citation statements)

References 9 publications

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“…Loss-of-function variants in SNX10 result in secondary impairment of V-ATPase and failure to acidify the resorption lacuna [ 13 ]. A homozygous ~70 kb deletion chr7:g.(26249558_26251671)-(26321193_26322492) in SNX10 identified by 1 M array comparative genomic hybridization was previously reported with osteopetrosis [ 14 ]. Our ~72 kb deletion of the noncoding region partially overlaps with the reported ∼70 kb deletion.…”

Section: Discussionmentioning

confidence: 99%

Genome sequencing identifies a large non-coding region deletion of SNX10 causing autosomal recessive osteopetrosis

et al. 2022

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Autosomal recessive osteopetrosis (ARO) is a rare genetic disorder caused by impaired osteoclast activity. In this study, we describe a 4-year-old boy with increased bone density due to osteopetrosis, autosomal recessive 8. Using genome sequencing, we identified a large deletion in the 5′-untranslated region (UTR) of SNX10 (sorting nexin 10), where the regulatory region of this gene is located. This large deletion resulted in the absence of the SNX10 transcript and led to abnormal osteoclast activity. SNX10 is one of the nine genes known to cause ARO, shown to interact with V-ATPase (vacuolar type H( + )-ATPase), as it plays an important role in bone resorption. Our study highlights the importance of regulatory regions in the 5′-UTR of SNX10 for its expression while also demonstrating the importance of genome sequencing for detecting large deletion of the regulatory region of SNX10.

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Section: Discussionmentioning

confidence: 99%

Genome sequencing identifies a large non-coding region deletion of SNX10 causing autosomal recessive osteopetrosis

et al. 2022

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“…c.152G>A; p.Arg51Gln, was identified in members of three consanguineous Palestinian families by Aker et al [22]. Since then, 13 additional bi-allelic loss-of-function variants, including nonsense, missense and splicing variants, have been reported within several studies (Figure 3) [21,[23][24][25][26][27][28][29]. Among these variants is a frameshift variant (c.212+1G>T) that was identified in patients suffering from Västerbottenian osteopetrosis, which refers to a cluster of cases in Västerbotten County (Sweden) with an increased disease incidence due to a founder effect [21,24].…”

Section: Snx10 Geneticsmentioning

confidence: 99%

Osteopetrosis associated with PLEKHM1 and SNX10 genes, both involved in osteoclast vesicular trafficking

Huybrechts

Hul²

2022

Bone

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“…Following the original discovery of the R51Q mutation in SNX10, other mutations in SNX10 , often in exons 3 and 4, have been linked to this disease in other geographical regions ( Mégarbané et al, 2013 ; Pangrazio et al, 2013 ; Simanovsky et al, 2016 ; Stattin et al, 2017 ; Baer et al, 2019 ; Kocak et al, 2019 ; Stepensky et al, 2019 ) (see Table 1 and Figure 2 ). Overall, it is estimated that 4.5% of the cases of ARO worldwide are caused by mutations in this gene ( Sobacchi et al, 2013 ; Palagano et al, 2018 ).…”

Section: The R51q Mutation In Sorting Nexin 10 – a Cause Of Aro In Palestinian Communities And Elsewherementioning

confidence: 99%

“…Recent evidence also suggests that synonymous mutations, which do not lead to an exchange of an amino acid or truncated protein and previously considered silent, can still cause symptoms of osteopetrosis ( Palagano et al, 2017 ). Mutations leading to an intermediate osteopetrosis form, not as severe as ARO nor as benign as the dominant autosomal form of osteopetrosis, have also been detected in SNX10 ( Stattin et al, 2017 ; Baer et al, 2019 ). Although the symptoms of this intermediate disease present during infancy, it does not require urgent intervention.…”

Section: The R51q Mutation In Sorting Nexin 10 – a Cause Of Aro In Palestinian Communities And Elsewherementioning

confidence: 99%

Sorting Nexin 10 as a Key Regulator of Membrane Trafficking in Bone-Resorbing Osteoclasts: Lessons Learned From Osteopetrosis

Elson

Stein

Rabie

et al. 2021

Front. Cell Dev. Biol.

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Bone homeostasis is a complex, multi-step process, which is based primarily on a tightly orchestrated interplay between bone formation and bone resorption that is executed by osteoblasts and osteoclasts (OCLs), respectively. The essential physiological balance between these cells is maintained and controlled at multiple levels, ranging from regulated gene expression to endocrine signals, yet the underlying cellular and molecular mechanisms are still poorly understood. One approach for deciphering the mechanisms that regulate bone homeostasis is the characterization of relevant pathological states in which this balance is disturbed. In this article we describe one such “error of nature,” namely the development of acute recessive osteopetrosis (ARO) in humans that is caused by mutations in sorting nexin 10 (SNX10) that affect OCL functioning. We hypothesize here that, by virtue of its specific roles in vesicular trafficking, SNX10 serves as a key selective regulator of the composition of diverse membrane compartments in OCLs, thereby affecting critical processes in the sequence of events that link the plasma membrane with formation of the ruffled border and with extracellular acidification. As a result, SNX10 determines multiple features of these cells either directly or, as in regulation of cell-cell fusion, indirectly. This hypothesis is further supported by the similarities between the cellular defects observed in OCLs form various models of ARO, induced by mutations in SNX10 and in other genes, which suggest that mutations in the known ARO-associated genes act by disrupting the same plasma membrane-to-ruffled border axis, albeit to different degrees. In this article, we describe the population genetics and spread of the original arginine-to-glutamine mutation at position 51 (R51Q) in SNX10 in the Palestinian community. We further review recent studies, conducted in animal and cellular model systems, that highlight the essential roles of SNX10 in critical membrane functions in OCLs, and discuss possible future research directions that are needed for challenging or substantiating our hypothesis.

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Intermediate autosomal recessive osteopetrosis with a large noncoding deletion in SNX10: A case report

Cited by 7 publications

References 9 publications

Genome sequencing identifies a large non-coding region deletion of SNX10 causing autosomal recessive osteopetrosis

Genome sequencing identifies a large non-coding region deletion of SNX10 causing autosomal recessive osteopetrosis

Osteopetrosis associated with PLEKHM1 and SNX10 genes, both involved in osteoclast vesicular trafficking

Sorting Nexin 10 as a Key Regulator of Membrane Trafficking in Bone-Resorbing Osteoclasts: Lessons Learned From Osteopetrosis

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