{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T18:51:39Z","timestamp":1791312699215,"version":"4.3.1"},"reference-count":40,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:00:00Z","timestamp":1791244800000},"content-version":"vor","delay-in-days":5,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Cellular Biochemistry"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Kenny\u2010Caffey syndrome type II (KCS2) is a rare genetic disorder characterized by skeletal abnormalities, impaired growth, and developmental delay. This study investigates a novel heterozygous FAM111A variant's role in a patient presenting with KCS2\u2010like features. An 11\u2010year\u2010old patient with clinical features consistent with KCS2\u2010like syndrome underwent whole exome sequencing, which identified a novel heterozygous variant in the FAM111A gene. In vitro experiments and protein structure analysis were performed to elucidate the contribution of this mutation to KCS2\u2010like syndrome. To confirm the diagnosis, whole exome sequencing revealed a novel heterozygous variant (c.405delA\/p.E136Sfs*3) in the FAM111A gene in an 11\u2010year\u2010old patient. Additionally, we found the clinical features of this patient were consistent with KCS2\u2010like syndrome. Our\n                    <jats:italic>in vitro<\/jats:italic>\n                    studies revealed that the variant led to a significant increase in necroptosis of osteoclasts. Furthermore, variant osteoclasts displayed a significant down\u2010regulation of autophagy, which may contribute to the onset of KCS2\u2010like syndrome. Consequently, the augmented necroptosis may result in the up\u2010regulation of inflammatory cytokines such as IL\u20101\u03b2, IL\u201017, IL\u201012p70, MCP\u20101, IFN\u2010\u03b3 and TNF\u2010\u03b1. Protein structure analysis suggests that the truncated FAM111A (p.E136Sfs*3) retains an ubiquitin\u2010like domain, which might explain the up\u2010regulated ubiquitination in variant osteoclasts. Therefore, the enhanced ubiquitination in variant osteoclasts may lead to the excessive degradation of intracellular proteins, resulting in irreversible necroptosis. Our findings suggest that the novel variant FAM111A (c.405delA) may be a pathogenic factor in KCS2\u2010like syndrome, likely through mechanisms involving increased necroptosis and inflammation. This expands understanding of FAM111A variant's role in skeletal and immune dysregulation.\n                  <\/jats:p>","DOI":"10.1002\/jcb.70132","type":"journal-article","created":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T18:11:21Z","timestamp":1791310281000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Novel FAM111A Frameshift Variant Associated With Osteoclast Necroptosis and KCS2\u2010like Syndrome"],"prefix":"10.1002","volume":"127","author":[{"given":"Ping","family":"Wu","sequence":"first","affiliation":[{"name":"Department of Pediatrics The First Affiliated Hospital of Guangzhou Medical University Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-0552-246X","authenticated-orcid":false,"given":"Xue","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Afffliated Hospital, Guangzhou Medical University Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Allergy, Immunology and Rheumatology, Guangzhou Women and Children's Medical Center Guangzhou Medical University Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanlan","family":"Zhong","sequence":"additional","affiliation":[{"name":"Department of Allergy, Immunology and Rheumatology, Guangzhou Women and Children's Medical Center Guangzhou Medical University Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-8128-8192","authenticated-orcid":false,"given":"Kexin","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Allergy, Immunology and Rheumatology, Guangzhou Women and Children's Medical Center Guangzhou Medical University Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suyun","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Allergy, Immunology and Rheumatology, Guangzhou Women and Children's Medical Center Guangzhou Medical University Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Song","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Allergy, Immunology and Rheumatology, Guangzhou Women and Children's Medical Center Guangzhou Medical University Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenbo","family":"Zhang","sequence":"additional","affiliation":[{"name":"Guangzhou University of Chinese Medicine Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Allergy, Immunology and Rheumatology, Guangzhou Women and Children's Medical Center Guangzhou Medical University Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Sports Medicine General Hospital of Ningxia Medical University Yinchuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiming","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Sports Medicine General Hospital of Ningxia Medical University Yinchuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5637-8331","authenticated-orcid":false,"given":"Chun Kwok","family":"Wong","sequence":"additional","affiliation":[{"name":"Department of Chemical Pathology The Chinese University of Hong Kong, Prince of Wales Hospital Hong Kong China"},{"name":"Institute of Chinese Medicine and State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants The Chinese University of Hong Kong Hong Kong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9853-7380","authenticated-orcid":false,"given":"Zhe","family":"Cai","sequence":"additional","affiliation":[{"name":"Department of Allergy, Immunology and Rheumatology, Guangzhou Women and Children's Medical Center Guangzhou Medical University Guangzhou Guangdong China"},{"name":"College of Bioscience and Biotechnology Hunan Agricultural University Changsha China"},{"name":"Yuelushan Laboratory Changsha China"},{"name":"Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center Guangzhou Medical University Guangzhou 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