Biallelic variants in four genes underlying recessive osteogenesis imperfecta

Hayat, Amir; Hussain, Shabir; Bilal, Muhammad; Kausar, Mehran; Almuzzaini, Bader; Abbas, Safdar; Tanveer, Adeena; Khan, Amjad; Siddiqi, Saima; Foo, Jia Nee; Ahmad, Farooq; Khan, Feroz; Khan, Bushra; Anees, Mariam; Mäkitie, Outi; Alfadhel, Majid; Ahmad, Wasim; Umair, Muhammad

doi:10.1016/j.ejmg.2020.103954

Cited by 30 publications

(28 citation statements)

References 36 publications

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“…While biallelic loss-offunction mutations led to severe autosomal recessive OI-like phenotype with severe short stature, fractures, deformities and in some instances, developmental defects in the central nervous system, heterozygous WNT1 mutations were reported to cause autosomal dominant osteoporosis [45,65,66]. Since then, several cases with recessive OI caused by WNT1 mutations have been reported [67][68][69][70], confirming the severe OI type III -like phenotype in these patients. Ptosis has been suggested as a specific hallmark of this disease [67].…”

Section: Wnt1supporting

confidence: 53%

Early-Onset Osteoporosis

Mäkitie

Zillikens

2021

Calcif Tissue Int

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Osteoporosis is a skeletal disorder with enhanced bone fragility, usually affecting the elderly. It is very rare in children and young adults and the definition is not only based on a low BMD (a Z-score < − 2.0 in growing children and a Z-score ≤ − 2.0 or a T-score ≤ − 2.5 in young adults) but also on the occurrence of fragility fractures and/or the existence of underlying chronic diseases or secondary factors such as use of glucocorticoids. In the absence of a known chronic disease, fragility fractures and low BMD should prompt extensive screening for secondary causes, which can be found in up to 90% of cases. When fragility fractures occur in childhood or young adulthood without an evident secondary cause, investigations should explore the possibility of an underlying monogenetic bone disease, where bone fragility is caused by a single variant in a gene that has a major role in the skeleton. Several monogenic forms relate to type I collagen, but other forms also exist. Loss-of-function variants in LRP5 and WNT1 may lead to early-onset osteoporosis. The X-chromosomal osteoporosis caused by PLS3 gene mutations affects especially males. Another recently discovered form relates to disturbed sphingolipid metabolism due to SGMS2 mutations, underscoring the complexity of molecular pathology in monogenic early-onset osteoporosis. Management of young patients consists of treatment of secondary factors, optimizing lifestyle factors including calcium and vitamin D and physical exercise. Treatment with bone-active medication should be discussed on a personalized basis, considering the severity of osteoporosis and underlying disease versus the absence of evidence on anti-fracture efficacy and potential harmful effects in pregnancy.

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Section: Wnt1supporting

confidence: 53%

Early-Onset Osteoporosis

Mäkitie

Zillikens

2021

Calcif Tissue Int

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“…5F, G ). Bent long bones have been described in a human patient homozygous for a recessive mutation in SP7 (c.1052delA, p.(Glu351Glyfs*19)) 48 , while vertebral column curvature has also been reported 49 , 50 , IVD changes have not been described to date. We contacted the Egyptian child with the SP7 mutation reported in 2010; 48 now 15 years old, the patient displayed 2–3 fractures per year and was unable to walk or stand.…”

Section: Resultsmentioning

confidence: 99%

“…The SP7 locus was also identified in a meta-analysis evaluating gene variants associated with BMD across the lifespan 47 . Mutations in SP7 cause recessive osteogenesis imperfecta (OI type XII), characterized by generalized osteopenia, recurrent fractures, bone deformities and bent bones 48 – 50 . Zebrafish sp7 −/− show frequent fractures in the ribs, skull abnormalities (Wormian bones) and tooth phenotype, similar to those found in human patients 31 , 51 .…”

Section: Resultsmentioning

confidence: 99%

3D assessment of intervertebral disc degeneration in zebrafish identifies changes in bone density that prime disc disease

et al. 2021

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Back pain is a common condition with a high social impact and represents a global health burden. Intervertebral disc disease (IVDD) is one of the major causes of back pain; no therapeutics are currently available to reverse this disease. The impact of bone mineral density (BMD) on IVDD has been controversial, with some studies suggesting osteoporosis as causative for IVDD and others suggesting it as protective for IVDD. Functional studies to evaluate the influence of genetic components of BMD in IVDD could highlight opportunities for drug development and repurposing. By taking a holistic 3D approach, we established an aging zebrafish model for spontaneous IVDD. Increased BMD in aging, detected by automated computational analysis, is caused by bone deformities at the endplates. However, aged zebrafish spines showed changes in bone morphology, microstructure, mineral heterogeneity, and increased fragility that resembled osteoporosis. Elements of the discs recapitulated IVDD symptoms found in humans: the intervertebral ligament (equivalent to the annulus fibrosus) showed disorganized collagen fibers and herniation, while the disc center (nucleus pulposus equivalent) showed dehydration and cellular abnormalities. We manipulated BMD in young zebrafish by mutating sp7 and cathepsin K, leading to low and high BMD, respectively. Remarkably, we detected IVDD in both groups, demonstrating that low BMD does not protect against IVDD, and we found a strong correlation between high BMD and IVDD. Deep learning was applied to high-resolution synchrotron µCT image data to analyze osteocyte 3D lacunar distribution and morphology, revealing a role of sp7 in controlling the osteocyte lacunar 3D profile. Our findings suggest potential avenues through which bone quality can be targeted to identify beneficial therapeutics for IVDD.

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“…[5] In this manuscript, we discuss the SPARC gene which has been linked to OI type XVII, with Mendozo-Londono et al, 2015, publishing the first paper identifying pathogenic variants in SPARC in 2 affected individuals and Hayat et al, 2020 recently describing two further affected individuals. [6,7] SPARC gene is located on chromosome 5 between bands q31 and q33. The encoded proteinalso called "osteonectin" -is necessary for calcification of the collagen in bone, synthesis of extracellular matrix and the promotion of changes to cell shape.…”

Section: Introductionmentioning

confidence: 99%

Expanding the phenotype of SPARC-related osteogenesis imperfecta: clinical findings in two patients with pathogenic variants in SPARC and literature review

et al. 2021

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BackgroundSecreted protein, acidic, cysteine rich (SPARC)-related osteogenesis imperfecta (OI), also referred to as OI type XVII, was first described in 2015, since then there has been only one further report of this form of OI. SPARC is located on chromosome 5 between bands q31 and q33. The encoded protein is necessary for calcification of the collagen in bone, synthesis of extracellular matrix and the promotion of changes to cell shape.MethodsWe describe a further two patients with previously unreported homozygous SPARC variants with OI: one splice site; one nonsense pathogenic variant. We present detailed information on the clinical and radiological phenotype and correlate this with their genotype. There are only two previous reports by Mendozo-Londono et al and Hayat et al with clinical descriptions of patients with SPARC variants.ResultsFrom the data we have obtained, common clinical features in individuals with OI type XVII caused by SPARC variants include scoliosis (5/5), vertebral compression fractures (5/5), multiple long bone fractures (5/5) and delayed motor development (3/3). Interestingly, 2/4 patients also had abnormal brain MRI, including high subcortical white matter changes, abnormal fluid-attenuated inversion in the para-atrial white matter and a large spinal canal from T10 to L1. Of significance, both patients reported here presented with significant neuromuscular weakness prompting early workup.ConclusionCommon phenotypic expressions include delayed motor development with neuromuscular weakness, scoliosis and multiple fractures. The data presented here broaden the phenotypic spectrum establishing similar patterns of neuromuscular presentation with a presumed diagnosis of ‘myopathy’.

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Biallelic variants in four genes underlying recessive osteogenesis imperfecta

Cited by 30 publications

References 36 publications

Early-Onset Osteoporosis

Early-Onset Osteoporosis

3D assessment of intervertebral disc degeneration in zebrafish identifies changes in bone density that prime disc disease

Expanding the phenotype of SPARC-related osteogenesis imperfecta: clinical findings in two patients with pathogenic variants in SPARC and literature review

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