Homozygosity for Frameshift Mutations in XYLT2 Result in a Spondylo-Ocular Syndrome with Bone Fragility, Cataracts, and Hearing Defects

Munns, Craig F; Fahiminiya, Somayyeh; Poudel, Nabin; Munteanu, Maria Cristina; Majewski, Jacek; Sillence, David; Metcalf, Jordan P.; Biggin, Andrew; Glorieux, Francis H.; Fassier, François; Rauch, Frank; Hinsdale, Myron E.

doi:10.1016/j.ajhg.2015.04.017

Cited by 68 publications

(75 citation statements)

References 24 publications

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“…PGs are involved in many vital biological processes and function as fundamental constitutes of complex extracellular matrices in various tissues involving cartilage, brain, tendons, corneas, and intervertebral discs . Mutations in genes that encode for enzymes involved in PG metabolism affect multiple organs and cause a spectrum of skeletal dysplasia syndromes with short stature, generalized osteoporosis, scoliosis, and several other findings …”

Section: Discussionmentioning

confidence: 99%

“…Only 3 patients from 2 families with spondyloocular syndrome and confirmed XYLT2 mutations have been reported thus far . As part of an ongoing research program on genetic determinants of early‐onset osteoporosis, we used whole‐exome sequencing in a consanguineous family with spondyloocular syndrome to further elucidate the genetic causes of the syndrome.…”

Section: Introductionmentioning

confidence: 99%

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Spondyloocular Syndrome: Novel Mutations in XYLT2 Gene and Expansion of the Phenotypic Spectrum

Taylan

Costantini

Coles

et al. 2016

Journal of Bone and Mineral Research

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Spondyloocular syndrome is an autosomal-recessive disorder with spinal compression fractures, osteoporosis, and cataract. Mutations in XYLT2, encoding isoform of xylosyltransferase, were recently identified as the cause of the syndrome. We report on 4 patients, 2 unrelated patients and 2 siblings, with spondyloocular syndrome and novel mutations in XYLT2. Exome sequencing revealed a homozygous nonsense mutation, NM_022167.3(XYLT2): c.2188C>T, resulting in a premature stop codon (p.Arg730 Ã ) in a female patient. The patient presents visual impairment, generalized osteoporosis, short stature with short trunk, spinal compression fractures, and increased intervertebral disc space and hearing loss. We extended our XYLT2 analysis to a cohort of 22 patients with generalized osteoporosis, mostly from consanguineous families. In this cohort, we found by Sanger sequencing 2 siblings and 1 single patient who were homozygous for missense mutations in the XYLT2 gene (p.Arg563Gly and p.Leu605Pro). The patients had osteoporosis, compression fractures, cataracts, and hearing loss. Bisphosphonate treatment in 1 patient resulted in almost complete normalization of vertebral structures by adolescence, whereas treatment response in the others was variable. This report together with a previous study shows that mutations in the XYLT2 gene result in a variable phenotype dominated by spinal osteoporosis, cataract, and hearing loss.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Spondyloocular Syndrome: Novel Mutations in XYLT2 Gene and Expansion of the Phenotypic Spectrum

Taylan

Costantini

Coles

et al. 2016

Journal of Bone and Mineral Research

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“…X-linked early-onset severe osteoporosis without other OI features (126) Mineralization regulation SERPINF1 Pigment epithelium-derived factor Yes Slowly progressively worsening OI; osteoid mineralization defect (no endochondral defect) ( (133) Linker enzyme deficiency XYLT2 Xylosyltransferase II ? Vertebral fractures, cataracts, heart defects (134) The noncollagenous proteins within bone have been suggested to have a range of functions, from the formation of collagen fibrils and initiation of mineral platelet formation, to mineral maturation and collagen cross-linking. (11) In addition, osteopontin and osteocalcin are proposed to have roles in energy dissipation at the microfibrillar level through the formation of dilatational voids (12) and, additionally for osteopontin, through the forming, loss, and reforming of sacrificial bonds with divalent cations such as calcium.…”

Section: Wnt1mentioning

confidence: 99%

Bone Material Properties in Osteogenesis Imperfecta

Bishop

2016

Journal of Bone and Mineral Research

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Osteogenesis imperfecta entrains changes at every level in bone tissue, from the disorganization of the collagen molecules and mineral platelets within and between collagen fibrils to the macroarchitecture of the whole skeleton. Investigations using an array of sophisticated instruments at multiple scale levels have now determined many aspects of the effect of the disease on the material properties of bone tissue. The brittle nature of bone in osteogenesis imperfecta reflects both increased bone mineralization density-the quantity of mineral in relation to the quantity of matrix within a specific bone volume-and altered matrix-matrix and matrix mineral interactions. Contributions to fracture resistance at multiple scale lengths are discussed, comparing normal and brittle bone. Integrating the available information provides both a better understanding of the effect of current approaches to treatment-largely improved architecture and possibly some macroscale toughening-and indicates potential opportunities for alternative strategies that can influence fracture resistance at longer-length scales.

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“…Currently, there is no review specifically addressing the patterns of visual impairment in OPPG and SOS. [19] The general management of OPPG by administration of bisphosphonates and the success thereof have been documented. [20] It has been recommended that patients with OPPG should begin treatment with bisphosphonates in the early years of life.…”

Section: The New Millenniummentioning

confidence: 99%

Osteoporosis-pseudoglioma syndrome in South Africa

Stephen

Roberts²

2016

S Afr Med J

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The osteoporosis-pseudoglioma syndrome (MIM 259770) is a rare autosomal recessive disorder in which bone fragility and frequent fractures are associated with serious ocular changes. The skeletal manifestations resemble those of osteogenesis imperfecta while hyperplasia of the vitreous, eye and corneal opacities often mimics the appearance of intraocular glioma. This disorder was previously reported in a South African family of Indian stock as 'the ocular form of osteogenesis imperfecta' . Terminological discussion followed and it was suggested that these individuals had osteoporosis-pseudoglioma syndrome. This article describes and depicts the manifestations of the disorder and discusses the nosology.

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Homozygosity for Frameshift Mutations in XYLT2 Result in a Spondylo-Ocular Syndrome with Bone Fragility, Cataracts, and Hearing Defects

Cited by 68 publications

References 24 publications

Spondyloocular Syndrome: Novel Mutations in XYLT2 Gene and Expansion of the Phenotypic Spectrum

Spondyloocular Syndrome: Novel Mutations in XYLT2 Gene and Expansion of the Phenotypic Spectrum

Bone Material Properties in Osteogenesis Imperfecta

Osteoporosis-pseudoglioma syndrome in South Africa

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