{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,12]],"date-time":"2026-11-12T18:30:52Z","timestamp":1794508252489,"version":"4.9.1"},"reference-count":32,"publisher":"BMJ","issue":"8","funder":[{"DOI":"10.13039\/100021036","name":"Turkish Pediatric association","doi-asserted-by":"crossref","award":["(grant number 04\/14.2.2019)"],"award-info":[{"award-number":["(grant number 04\/14.2.2019)"]}],"id":[{"id":"10.13039\/100021036","id-type":"DOI","asserted-by":"crossref"}]},{"name":"the Scientific and Technological Research Council of Turkey","award":["(grant number 217S378 to B.T.)"],"award-info":[{"award-number":["(grant number 217S378 to B.T.)"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2022,12,10]]},"published-print":{"date-parts":[[2023,8]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Osteogenesis imperfecta (OI) is a heterogeneous group of inherited disorders characterised by susceptibility to fractures, primarily due to defects in type 1 collagen. The aim of this study is to present a novel OI phenotype and its causative candidate gene.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Whole-exome sequencing and clinical evaluation were performed in five patients from two unrelated families. <jats:italic>PHLDB1<\/jats:italic> mRNA expression in blood and fibroblasts was investigated by real-time PCR, and western blot analysis was further performed on skin fibroblasts.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>The common findings among the five affected children were recurrent fractures and\/or osteopaenia, platyspondyly, short and bowed long bones, and widened metaphyses. Metaphyseal and vertebral changes regressed after early childhood, and no fractures occurred under bisphosphonate treatment. We identified biallelic NM_001144758.3:c.2392dup and NM_001144758.3:c.2690_2693del pathogenic variants in <jats:italic>PHLDB1<\/jats:italic> in the affected patients, respectively, in the families; parents were heterozygous for these variants. <jats:italic>PHLDB1<\/jats:italic> encodes pleckstrin homology-like domain family B member-1 (PHLDB1) protein, which has a role in insulin-dependent Akt phosphorylation. Compared with controls, a decrease in the expression levels of <jats:italic>PHLDB1<\/jats:italic> in the blood and skin fibroblast samples was detected. Western blot analysis of cultured fibroblasts further confirmed the loss of PHLDB1.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Two biallelic frameshift variants in the candidate gene <jats:italic>PHLDB1<\/jats:italic> were identified in independent families with a novel, mild-type, autosomal recessive OI. The demonstration of decreased <jats:italic>PHLDB1<\/jats:italic> mRNA expression levels in blood and fibroblast samples supports the hypothesis that <jats:italic>PHLDB1<\/jats:italic> pathogenic variants are causative for the observed phenotype.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jmg-2022-108763","type":"journal-article","created":{"date-parts":[[2022,12,21]],"date-time":"2022-12-21T13:20:38Z","timestamp":1671628838000},"page":"819-826","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":14,"title":["Biallelic frameshift variants in <i>PHLDB1<\/i> cause mild-type osteogenesis imperfecta with regressive spondylometaphyseal changes"],"prefix":"10.1136","volume":"60","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9620-5021","authenticated-orcid":false,"given":"Beyhan","family":"Tuysuz","sequence":"first","affiliation":[{"name":"Department of Pediatric Genetics, Istanbul University-Cerrahpasa, Cerrahpasa Medical Faculty, Istanbul, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dilek","family":"Uludag Alkaya","sequence":"additional","affiliation":[{"name":"Department of Pediatric Genetics, Istanbul University-Cerrahpasa, Cerrahpasa Medical Faculty, Istanbul, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filiz","family":"Geyik","sequence":"additional","affiliation":[{"name":"Department of Pediatric Genetics, Istanbul University-Cerrahpasa, Cerrahpasa Medical Faculty, Istanbul, Turkey"},{"name":"Department of Genetics, Aziz Sancar Experimental Medicine Research Institute, Istanbul University, Istanbul, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Merve","family":"Alayl\u0131o\u011flu","sequence":"additional","affiliation":[{"name":"Institute of Neurological Sciences, Brain and Neurodegenerative Disorders Research Laboratory, Istanbul University-Cerrahpasa, Istanbul, 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