{"entity": "journal", "iuid": "9314b4ce8d014c3a94b815be08107596", "timestamp": "2026-07-10T07:43:25.176Z", "links": {"self": {"href": "https://publications.scilifelab.se/journal/J.%20Bone%20Miner.%20Res..json"}, "display": {"href": "https://publications.scilifelab.se/journal/J.%20Bone%20Miner.%20Res."}}, "title": "J. Bone Miner. Res.", "issn": "1523-4681", "issn-l": "0884-0431", "publications_count": 8, "publications": [{"entity": "publication", "iuid": "74e6bcf9f810455aafeb36c2253b4848", "links": {"self": {"href": "https://publications.scilifelab.se/publication/74e6bcf9f810455aafeb36c2253b4848.json"}, "display": {"href": "https://publications.scilifelab.se/publication/74e6bcf9f810455aafeb36c2253b4848"}}, "title": "Gene-based association analysis of a large patient cohort provides insights into genetics of atypical femur fractures.", "authors": [{"family": "Zhou", "given": "Wei", "initials": "W", "orcid": "0000-0002-6748-6303", "researcher": {"href": "https://publications.scilifelab.se/researcher/6f7e9b3a6ffa45dba854cb6acf59739b.json"}}, {"family": "\u00c5s", "given": "Joel", "initials": "J"}, {"family": "Shore-Lorenti", "given": "Catherine", "initials": "C"}, {"family": "Nguyen", "given": "Hanh H", "initials": "HH", "orcid": "0000-0002-8846-6168", "researcher": {"href": "https://publications.scilifelab.se/researcher/6a4cb30d23e54b8c8b328859ead81ba7.json"}}, {"family": "van de Laarschot", "given": "Denise M", "initials": "DM"}, {"family": "Sztal-Mazer", "given": "Shoshana", "initials": "S"}, {"family": "Grill", "given": "Vivian", "initials": "V"}, {"family": "Girgis", "given": "Christian M", "initials": "CM"}, {"family": "Stricker", "given": "Bruno H Ch", "initials": "BHC"}, {"family": "van der Eerden", "given": "Bram C J", "initials": "BCJ"}, {"family": "Thakker", "given": "Rajesh V", "initials": "RV"}, {"family": "Appelman-Dijkstra", "given": "Natasha M", "initials": "NM", "orcid": "0000-0001-5035-127X", "researcher": {"href": "https://publications.scilifelab.se/researcher/5f26fbf2e8d14f8ebf65acd9e22d7b41.json"}}, {"family": "Wadelius", "given": "Mia", "initials": "M"}, {"family": "Clifton-Bligh", "given": "Roderick J", "initials": "RJ"}, {"family": "Hallberg", "given": "P\u00e4r", "initials": "P"}, {"family": "Verkerk", "given": "Annemieke J M H", "initials": "AJMH"}, {"family": "van Rooij", "given": "Jeroen G J", "initials": "JGJ"}, {"family": "Ebeling", "given": "Peter R", "initials": "PR"}, {"family": "Zillikens", "given": "M Carola", "initials": "MC", "orcid": "0000-0001-9186-3423", "researcher": {"href": "https://publications.scilifelab.se/researcher/8c71c257a4de4ac7b59381237a0fa500.json"}}], "type": "journal article", "published": "2024-09-02", "journal": {"title": "J. Bone Miner. Res.", "issn": "1523-4681", "volume": "39", "issue": "9", "pages": "1315-1326", "issn-l": "0884-0431"}, "abstract": "Several small genetic association studies have been conducted for atypical femur fracture (AFF) without replication of results. We assessed previously implicated and novel genes associated with AFFs in a larger set of unrelated AFF cases using whole exome sequencing (WES). We performed gene-based association analysis on 139 European AFF cases and 196 controls matched for bisphosphonate use. We tested all rare, protein-altering variants using both candidate gene and hypothesis-free approaches. In the latter, genes suggestively associated with AFFs (uncorrected p-values <.01) were investigated in a Swedish whole-genome sequencing replication study and assessed in 46 non-European cases. In the candidate gene analysis, PLOD2 showed a suggestive signal. The hypothesis-free approach revealed 10 tentative associations, with XRN2, SORD, and PLOD2 being the most likely candidates for AFF. XRN2 and PLOD2 showed consistent direction of effect estimates in the replication analysis, albeit not statistically significant. Three SNPs associated with SORD expression according to the GTEx portal were in linkage disequilibrium (R2 \u2265 0.2) with an SNP previously reported in a genome-wide association study of AFF. The prevalence of carriers of variants for both PLOD2 and SORD was higher in Asian versus European cases. While we did not identify genes enriched for damaging variants, we found suggestive evidence of a role for XRN2, PLOD2, and SORD, which requires further investigation. Our findings indicate that genetic factors responsible for AFFs are not widely shared among AFF cases. The study provides a stepping-stone for future larger genetic studies of AFF.", "doi": "10.1093/jbmr/zjae122", "pmid": "39126371", "labels": {"NGI Uppsala (SNP&SEQ Technology Platform)": "Service", "NGI Short read": "Service", "National Genomics Infrastructure": "Service"}, "xrefs": [{"db": "pmc", "key": "PMC11371903"}, {"db": "pii", "key": "7731319"}], "notes": [], "created": "2024-10-21T11:12:51.933Z", "modified": "2024-10-21T11:13:04.359Z"}, {"entity": "publication", "iuid": "af488245ad1b47a38b9e0689bb99e1f7", "links": {"self": {"href": "https://publications.scilifelab.se/publication/af488245ad1b47a38b9e0689bb99e1f7.json"}, "display": {"href": "https://publications.scilifelab.se/publication/af488245ad1b47a38b9e0689bb99e1f7"}}, "title": "Al-Gazali Skeletal Dysplasia Constitutes the Lethal End of ADAMTSL2-Related Disorders.", "authors": [{"family": "Batkovskyte", "given": "Dominyka", "initials": "D"}, {"family": "McKenzie", "given": "Fiona", "initials": "F"}, {"family": "Taylan", "given": "Fulya", "initials": "F", "orcid": "0000-0002-2907-0235", "researcher": {"href": "https://publications.scilifelab.se/researcher/c250909cc40f42ff9d6e2f640d12451b.json"}}, {"family": "Simsek-Kiper", "given": "Pelin Ozlem", "initials": "PO"}, {"family": "Nikkel", "given": "Sarah M", "initials": "SM"}, {"family": "Ohashi", "given": "Hirofumi", "initials": "H"}, {"family": "Stevenson", "given": "Roger E", "initials": "RE"}, {"family": "Ha", "given": "Thuong", "initials": "T"}, {"family": "Cavalcanti", "given": "Denise P", "initials": "DP"}, {"family": "Miyahara", "given": "Hiroyuki", "initials": "H"}, {"family": "Skinner", "given": "Steven A", "initials": "SA"}, {"family": "Aguirre", "given": "Miguel A", "initials": "MA"}, {"family": "Ak\u00e7\u00f6ren", "given": "Z\u00fchal", "initials": "Z"}, {"family": "Utine", "given": "Gulen Eda", "initials": "GE"}, {"family": "Chiu", "given": "Tillie", "initials": "T"}, {"family": "Shimizu", "given": "Kenji", "initials": "K", "orcid": "0000-0002-2732-8722", "researcher": {"href": "https://publications.scilifelab.se/researcher/3ed999c64ff94fe4826ce8379029a1b2.json"}}, {"family": "Hammarsj\u00f6", "given": "Anna", "initials": "A"}, {"family": "Boduroglu", "given": "Koray", "initials": "K"}, {"family": "Moore", "given": "Hannah W", "initials": "HW"}, {"family": "Louie", "given": "Raymond J", "initials": "RJ"}, {"family": "Arts", "given": "Peer", "initials": "P"}, {"family": "Merrihew", "given": "Allie N", "initials": "AN"}, {"family": "Babic", "given": "Milena", "initials": "M"}, {"family": "Jackson", "given": "Matilda R", "initials": "MR"}, {"family": "Papadogiannakis", "given": "Nikos", "initials": "N"}, {"family": "Lindstrand", "given": "Anna", "initials": "A"}, {"family": "Nordgren", "given": "Ann", "initials": "A"}, {"family": "Barnett", "given": "Christopher P", "initials": "CP"}, {"family": "Scott", "given": "Hamish S", "initials": "HS", "orcid": "0000-0002-5813-631X", "researcher": {"href": "https://publications.scilifelab.se/researcher/dabd7f9a75aa49a0856cd3f697739a11.json"}}, {"family": "Chagin", "given": "Andrei S", "initials": "AS"}, {"family": "Nishimura", "given": "Gen", "initials": "G"}, {"family": "Grigelioniene", "given": "Giedre", "initials": "G", "orcid": "0000-0001-9601-3137", "researcher": {"href": "https://publications.scilifelab.se/researcher/684864357acd490cb627f38fed3b82a4.json"}}], "type": "journal article", "published": "2023-05-00", "journal": {"title": "J. Bone Miner. Res.", "issn": "1523-4681", "volume": "38", "issue": "5", "pages": "692-706", "issn-l": "0884-0431"}, "abstract": "Lethal short-limb skeletal dysplasia Al-Gazali type (OMIM %601356), also called dysplastic cortical hyperostosis, Al-Gazali type, is an ultra-rare disorder previously reported in only three unrelated individuals. The genetic etiology for Al-Gazali skeletal dysplasia has up until now been unknown. Through international collaborative efforts involving seven clinical centers worldwide, a cohort of nine patients with clinical and radiographic features consistent with short-limb skeletal dysplasia Al-Gazali type was collected. The affected individuals presented with moderate intrauterine growth restriction, relative macrocephaly, hypertrichosis, large anterior fontanelle, short neck, short and stiff limbs with small hands and feet, severe brachydactyly, and generalized bone sclerosis with mild platyspondyly. Biallelic disease-causing variants in ADAMTSL2 were detected using massively parallel sequencing (MPS) and Sanger sequencing techniques. Six individuals were compound heterozygous and one individual was homozygous for pathogenic variants in ADAMTSL2. In one of the families, pathogenic variants were detected in parental samples only. Overall, this study sheds light on the genetic cause of Al-Gazali skeletal dysplasia and identifies it as a semi-lethal part of the spectrum of ADAMTSL2-related disorders. Furthermore, we highlight the importance of meticulous analysis of the pseudogene region of ADAMTSL2 where disease-causing variants might be located. \u00a9 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).", "doi": "10.1002/jbmr.4799", "pmid": "36896612", "labels": {"Clinical Genomics Stockholm": "Service", "Bioinformatics Support for Computational Resources": "Service", "Clinical Genomics": "Service"}, "xrefs": [], "notes": [], "created": "2023-12-04T11:30:24.900Z", "modified": "2024-01-16T13:48:33.517Z"}, {"entity": "publication", "iuid": "f3cf1abbd62644c3be5958421f8c8892", "links": {"self": {"href": "https://publications.scilifelab.se/publication/f3cf1abbd62644c3be5958421f8c8892.json"}, "display": {"href": "https://publications.scilifelab.se/publication/f3cf1abbd62644c3be5958421f8c8892"}}, "title": "SLC4A2 Deficiency Causes a New Type of Osteopetrosis.", "authors": [{"family": "Xue", "given": "Jing-Yi", "initials": "JY"}, {"family": "Grigelioniene", "given": "Giedre", "initials": "G"}, {"family": "Wang", "given": "Zheng", "initials": "Z"}, {"family": "Nishimura", "given": "Gen", "initials": "G"}, {"family": "Iida", "given": "Aritoshi", "initials": "A"}, {"family": "Matsumoto", "given": "Naomichi", "initials": "N"}, {"family": "Tham", "given": "Emma", "initials": "E"}, {"family": "Miyake", "given": "Noriko", "initials": "N"}, {"family": "Ikegawa", "given": "Shiro", "initials": "S"}, {"family": "Guo", "given": "Long", "initials": "L", "orcid": "0000-0002-9660-6941", "researcher": {"href": "https://publications.scilifelab.se/researcher/4c06210f2dbf4afab673cccf88d06aea.json"}}], "type": "journal article", "published": "2021-10-20", "journal": {"title": "J. Bone Miner. Res.", "issn": "1523-4681", "issn-l": "0884-0431"}, "abstract": "Osteopetrosis is a group of rare inherited skeletal disorders characterized by a marked increase in bone density due to deficient bone resorption. Pathogenic variants in several genes involved in osteoclast differentiation and/or function have been reported to cause osteopetrosis. Solute carrier family 4 member 2 (SLC4A2, encoding anion exchanger 2) plays an important role in osteoclast differentiation and function by exchange of Cl- with HCO3 - . Biallelic Slc4a2 loss-of-function mutations in mice and cattle lead to osteopetrosis with osteoclast deficiency; however, pathogenic SLC4A2 variants in humans have not been reported. In this study, we describe a patient with autosomal recessive osteopetrosis due to biallelic pathogenic variants in SLC4A2. We identified novel compound heterozygous variants in SLC4A2 (NM_003040.4: c.556G>A [p.A186T] and c.1658T>C [p.V553A]) by exome sequencing. The measurement of intracellular Cl- showed that the variants decrease the anion exchange activity of SLC4A2. The impact of the variants on osteoclast differentiation was assessed by a gene knockout-rescue system using a mouse macrophage cell line, RAW 264.7. The Slc4a2-knockout cells show impaired osteoclastogenesis, which was rescued by the wild-type SLC4A2, but not by the mutant SLC4A2s. Immunofluorescence and pit assay revealed that the mutant SLC4A2s leads to abnormal podosome belt formation with impaired bone absorption. This is the first report on an individual affected by SLC4A2-associated osteopetrosis (osteopetrosis, Ikegawa type). With functional studies, we prove that the variants lead to SLC4A2 dysfunction, which altogether supports the importance of SLC4A2 in human osteoclast differentiation. \u00a9 2021 American Society for Bone and Mineral Research (ASBMR).", "doi": "10.1002/jbmr.4462", "pmid": "34668226", "labels": {"Clinical Genomics Stockholm": "Service", "Clinical Genomics": "Service"}, "xrefs": [], "notes": [], "created": "2021-11-20T12:31:06.796Z", "modified": "2021-11-20T12:31:06.850Z"}, {"entity": "publication", "iuid": "b5ee1dafcd6645839c985b356b49ce86", "links": {"self": {"href": "https://publications.scilifelab.se/publication/b5ee1dafcd6645839c985b356b49ce86.json"}, "display": {"href": "https://publications.scilifelab.se/publication/b5ee1dafcd6645839c985b356b49ce86"}}, "title": "Serum 25-hydroxyvitamin D is associated with fracture risk only during periods of seasonally high levels in women with a high body mass index.", "authors": [{"family": "Micha\u00eblsson", "given": "Karl", "initials": "K", "orcid": "0000-0003-2815-1217", "researcher": {"href": "https://publications.scilifelab.se/researcher/eff63868e95240f695d47e871e31947f.json"}}, {"family": "Byberg", "given": "Liisa", "initials": "L", "orcid": "0000-0002-4421-6466", "researcher": {"href": "https://publications.scilifelab.se/researcher/b3b127d82f1a4c35bb73f32658c924ee.json"}}, {"family": "Svennblad", "given": "Bodil", "initials": "B"}, {"family": "Larsson", "given": "Susanna C", "initials": "SC"}, {"family": "Baron", "given": "John A", "initials": "JA"}, {"family": "Melhus", "given": "H\u00e5kan", "initials": "H"}], "type": "journal article", "published": "2021-10-00", "journal": {"title": "J. Bone Miner. Res.", "issn": "1523-4681", "volume": "36", "issue": "10", "pages": "1957-1966", "issn-l": "0884-0431"}, "abstract": "Serum 25-hydroxyvitamin D (S-25OHD) is used to assess vitamin D status and is known to be affected by season and fat mass. Because these factors are often ignored when interpreting S-25OHD, assessment of vitamin D associations with disease outcomes may be distorted. We aimed to investigate the impact of season of blood draw and fat mass on the association of S25OHD with fracture risk. We enrolled 5000 women, mean \u00b1 SD age 68 \u00b1 7 years, with dual-energy x-ray absorptiometry (DXA) scans and blood collection in a population-based cohort. Proportional hazards regression, stratified by season and fat mass, was used to determine hazard ratios (HRs) of fracture according to categories of S-25OHD. Our secondary exposures were serum 1,25-dihydroxycholecalciferol (1,25-(OH)2 D3 ), the most active vitamin D metabolite and plasma parathyroid hormone (P-PTH). During an average of 9.2 years of follow-up, 1080 women had a fracture. Women with S-25OHD <30 nmol/L drawn during sunny months (May-October) had a multivariable-adjusted fracture HR of 2.06 (95% CI, 1.27-3.35) compared with those with S-25OHD >60 nmol/L; those with S-25OHD 30-40 nmol/L had an HR of 1.59 (95% CI, 1.12-2.26). In contrast, S-25OHD drawn during November through April was unrelated to fracture risk. The increased risk with low sunny season S-25OHD was seen only among women with body mass index (BMI) \u226525 kg/m2 or fat mass index (FMI) \u22659.8 kg/m2 . High fat mass and low S-25OHD were independently related to lower S-1,25-dihydroxycholecalciferol, which itself predicted fracture risk with samples collected during the sunny season. Irrespective of season, P-PTH was unrelated to fracture risk. We conclude that S-25OHD is associated with fracture risk only if drawn during periods of seasonally high levels in women with a high BMI. These results have implications for the evaluation of vitamin D status and can explain the lack of effect seen with vitamin D supplementation in many fracture trials. \u00a9 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).", "doi": "10.1002/jbmr.4400", "pmid": "34173270", "labels": {"Bioinformatics Support for Computational Resources": "Service"}, "xrefs": [], "notes": [], "created": "2022-11-09T16:00:00.641Z", "modified": "2024-01-16T13:48:38.333Z"}, {"entity": "publication", "iuid": "7236f7508d984367aa99dee5e8625628", "links": {"self": {"href": "https://publications.scilifelab.se/publication/7236f7508d984367aa99dee5e8625628.json"}, "display": {"href": "https://publications.scilifelab.se/publication/7236f7508d984367aa99dee5e8625628"}}, "title": "Genotype-Phenotype Correlation of PLOD2 Skeletal Dysplasias Using Structural Information.", "authors": [{"family": "Tham", "given": "Emma", "initials": "E"}, {"family": "Grigelionis", "given": "Gintautas", "initials": "G"}, {"family": "Hammarsj\u00f6", "given": "Anna", "initials": "A"}, {"family": "Grigelioniene", "given": "Giedre", "initials": "G"}], "type": "letter", "published": "2018-07-00", "journal": {"volume": "33", "issn": "1523-4681", "issue": "7", "pages": "1377-1378", "title": "J. Bone Miner. Res.", "issn-l": "0884-0431"}, "abstract": null, "doi": "10.1002/jbmr.3460", "pmid": "29878396", "labels": {"Clinical Genomics Stockholm": "Service", "Bioinformatics Support for Computational Resources": "Service", "Clinical Genomics": "Service"}, "xrefs": [], "notes": [], "created": "2018-10-29T09:07:41.698Z", "modified": "2024-01-16T13:48:46.055Z"}, {"entity": "publication", "iuid": "d24174e71c854ddfb3f607e66dfac13e", "links": {"self": {"href": "https://publications.scilifelab.se/publication/d24174e71c854ddfb3f607e66dfac13e.json"}, "display": {"href": "https://publications.scilifelab.se/publication/d24174e71c854ddfb3f607e66dfac13e"}}, "title": "PLS3 Deletions Lead to Severe Spinal Osteoporosis and Disturbed Bone Matrix Mineralization.", "authors": [{"family": "K\u00e4mpe", "given": "Anders J", "initials": "AJ"}, {"family": "Costantini", "given": "Alice", "initials": "A"}, {"family": "Levy-Shraga", "given": "Yael", "initials": "Y"}, {"family": "Zeitlin", "given": "Leonid", "initials": "L"}, {"family": "Roschger", "given": "Paul", "initials": "P"}, {"family": "Taylan", "given": "Fulya", "initials": "F"}, {"family": "Lindstrand", "given": "Anna", "initials": "A"}, {"family": "Paschalis", "given": "Eleftherios P", "initials": "EP"}, {"family": "Gamsjaeger", "given": "Sonja", "initials": "S"}, {"family": "Raas-Rothschild", "given": "Annick", "initials": "A"}, {"family": "H\u00f6vel", "given": "Matthias", "initials": "M"}, {"family": "Jiao", "given": "Hong", "initials": "H"}, {"family": "Klaushofer", "given": "Klaus", "initials": "K"}, {"family": "Grasemann", "given": "Corinna", "initials": "C"}, {"family": "M\u00e4kitie", "given": "Outi", "initials": "O"}], "type": "journal article", "published": "2017-08-04", "journal": {"volume": null, "issn": "1523-4681", "issue": null, "title": "J. Bone Miner. Res.", "issn-l": "0884-0431"}, "abstract": "Mutations in the PLS3 gene, encoding Plastin 3, were described in 2013 as a cause for X-linked primary bone fragility in children. The specific role of PLS3 in bone metabolism remains inadequately understood. Here we describe for the first time PLS3 deletions as the underlying cause for childhood-onset primary osteoporosis in 3 boys from 2 families. We carried out thorough clinical, radiological, and bone tissue analyses to explore the consequences of these deletions and to further elucidate the role of PLS3 in bone homeostasis. In family 1, the 2 affected brothers had a deletion of exons 4-16 (NM_005032) in PLS3, inherited from their healthy mother. In family 2, the index patient had a deletion involving the entire PLS3 gene (exons 1-16), inherited from his mother who had osteoporosis. The 3 patients presented in early childhood with severe spinal compression fractures involving all vertebral bodies. The 2 brothers in family 1 also displayed subtle dysmorphic facial features and both had developed a myopathic gait. Extensive analyses of a transiliac bone biopsy from 1 patient showed a prominent increase in osteoid volume, osteoid thickness, and in mineralizing lag time. Results from quantitative backscattered electron imaging and Raman microspectroscopy showed a significant hypomineralization of the bone. Together our results indicate that PLS3 deletions lead to severe childhood-onset osteoporosis resulting from defective bone matrix mineralization, suggesting a specific role for PLS3 in the mineralization process. \u00a9 2017 American Society for Bone and Mineral Research.", "doi": "10.1002/jbmr.3233", "pmid": "28777485", "labels": {"National Genomics Infrastructure": "Service", "NGI Stockholm (Genomics Applications)": "Service", "NGI Stockholm (Genomics Production)": "Service", "Bioinformatics Support for Computational Resources": "Service"}, "xrefs": [], "notes": [], "created": "2017-11-03T16:19:23.777Z", "modified": "2024-01-16T13:48:47.646Z"}, {"entity": "publication", "iuid": "3a1cc06125b84310aade5d4e82d2ae12", "links": {"self": {"href": "https://publications.scilifelab.se/publication/3a1cc06125b84310aade5d4e82d2ae12.json"}, "display": {"href": "https://publications.scilifelab.se/publication/3a1cc06125b84310aade5d4e82d2ae12"}}, "title": "A Large Inversion Involving GNAS Exon A/B and All Exons Encoding Gs\u03b1 Is Associated With Autosomal Dominant Pseudohypoparathyroidism Type Ib (PHP1B).", "authors": [{"family": "Grigelioniene", "given": "Giedre", "initials": "G"}, {"family": "Nevalainen", "given": "Pasi I", "initials": "PI"}, {"family": "Reyes", "given": "Monica", "initials": "M"}, {"family": "Thiele", "given": "Susanne", "initials": "S"}, {"family": "Tafaj", "given": "Olta", "initials": "O"}, {"family": "Molinaro", "given": "Angelo", "initials": "A"}, {"family": "Takatani", "given": "Rieko", "initials": "R"}, {"family": "Ala-Houhala", "given": "Marja", "initials": "M"}, {"family": "Nilsson", "given": "Daniel", "initials": "D"}, {"family": "Eisfeldt", "given": "Jesper", "initials": "J"}, {"family": "Lindstrand", "given": "Anna", "initials": "A"}, {"family": "Kottler", "given": "Marie-Laure", "initials": "ML"}, {"family": "M\u00e4kitie", "given": "Outi", "initials": "O"}, {"family": "J\u00fcppner", "given": "Harald", "initials": "H"}], "type": "case reports", "published": "2017-04-00", "journal": {"volume": "32", "issn": "1523-4681", "issue": "4", "pages": "776-783", "title": "J. Bone Miner. Res.", "issn-l": "0884-0431"}, "abstract": "Pseudohypoparathyroidism type Ib (PHP1B) is characterized primarily by resistance to parathyroid hormone (PTH) and thus hypocalcemia and hyperphosphatemia, in most cases without evidence for Albright hereditary osteodystrophy (AHO). PHP1B is associated with epigenetic changes at one or several differentially-methylated regions (DMRs) within GNAS, which encodes the \u03b1-subunit of the stimulatory G protein (Gs\u03b1) and splice variants thereof. Heterozygous, maternally inherited STX16 or GNAS deletions leading to isolated loss-of-methylation (LOM) at exon A/B alone or at all maternal DMRs are the cause of autosomal dominant PHP1B (AD-PHP1B). In this study, we analyzed three affected individuals, the female proband and her two sons. All three revealed isolated LOM at GNAS exon A/B, whereas the proband's healthy maternal grandmother and uncle showed normal methylation at this locus. Haplotype analysis was consistent with linkage to the STX16/GNAS region, yet no deletion could be identified. Whole-genome sequencing of one of the patients revealed a large heterozygous inversion (1,882,433 bp). The centromeric breakpoint of the inversion is located 7,225 bp downstream of GNAS exon XL, but its DMR showed no methylation abnormality, raising the possibility that the inversion disrupts a regulatory element required only for establishing or maintaining exon A/B methylation. Because our three patients presented phenotypes consistent with PHP1B, and not with PHP1A, the Gs\u03b1 promoter is probably unaffected by the inversion. Our findings expand the spectrum of genetic mutations that lead to LOM at exon A/B alone and thus biallelic expression of the transcript derived from this alternative first GNAS exon. \u00a9 2017 American Society for Bone and Mineral Research.", "doi": "10.1002/jbmr.3083", "pmid": "28084650", "labels": {"National Genomics Infrastructure": "Service", "NGI Stockholm (Genomics Applications)": "Service", "NGI Stockholm (Genomics Production)": "Service", "Clinical Genomics Stockholm": "Service", "Bioinformatics Support for Computational Resources": "Service", "Clinical Genomics": "Service"}, "xrefs": [{"db": "pmc", "key": "PMC5395346"}, {"db": "mid", "key": "NIHMS843464"}], "notes": [], "created": "2017-11-03T12:53:35.193Z", "modified": "2024-01-16T13:48:48.221Z"}, {"entity": "publication", "iuid": "655d9c88a16e40798a9d335394eb0836", "links": {"self": {"href": "https://publications.scilifelab.se/publication/655d9c88a16e40798a9d335394eb0836.json"}, "display": {"href": "https://publications.scilifelab.se/publication/655d9c88a16e40798a9d335394eb0836"}}, "title": "Spondyloocular Syndrome: Novel Mutations in XYLT2 Gene and Expansion of the Phenotypic Spectrum.", "authors": [{"family": "Taylan", "given": "Fulya", "initials": "F"}, {"family": "Costantini", "given": "Alice", "initials": "A"}, {"family": "Coles", "given": "Nicole", "initials": "N"}, {"family": "Pekkinen", "given": "Minna", "initials": "M"}, {"family": "H\u00e9on", "given": "Elise", "initials": "E"}, {"family": "\u015e\u0131klar", "given": "Zeynep", "initials": "Z"}, {"family": "Berbero\u011flu", "given": "Merih", "initials": "M"}, {"family": "K\u00e4mpe", "given": "Anders", "initials": "A"}, {"family": "K\u0131yk\u0131m", "given": "Ertu\u011frul", "initials": "E"}, {"family": "Grigelioniene", "given": "Giedre", "initials": "G"}, {"family": "T\u00fcys\u00fcz", "given": "Beyhan", "initials": "B"}, {"family": "M\u00e4kitie", "given": "Outi", "initials": "O"}], "type": "journal article", "published": "2016-08-00", "journal": {"volume": "31", "issn": "1523-4681", "issue": "8", "pages": "1577-1585", "title": "J. Bone Miner. Res.", "issn-l": "0884-0431"}, "abstract": "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*) 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. \u00a9 2016 American Society for Bone and Mineral Research.", "doi": "10.1002/jbmr.2834", "pmid": "26987875", "labels": {"National Genomics Infrastructure": "Service", "NGI Stockholm (Genomics Applications)": "Service", "NGI Stockholm (Genomics Production)": "Service", "Bioinformatics Support for Computational Resources": "Service"}, "xrefs": [], "notes": [], "created": "2017-05-03T12:59:45.537Z", "modified": "2024-01-16T13:48:49.688Z"}], "created": "2017-05-09T09:12:17.385Z", "modified": "2020-11-27T13:14:04.504Z"}