title: Filamin B Loss-of-Function Mutation in Dimerization Domain Causes Autosomal-Recessive Spondylocarpotarsal Synostosis Syndrome with Rib Anomalies.
abstract: Spondylocarpotarsal synostosis syndrome (SCT) is a distinct group of disorders characterized by short stature, disrupted vertebral segmentation with vertebral fusion, scoliosis, lordosis, carpal/tarsal synostosis, and lack of rib anomalies. Mutations in filamin B (FLNB) and MYH3 have been reported for autosomal-recessive and autosomal-dominant SCT, respectively. We present a family with two patients suffering from autosomal-recessive SCT with rib anomalies, including malalignment, crowding, and uneven size and shape of ribs. Whole-exome sequencing revealed a novel p.S2542Lfs*82 (c.7621dup) frameshift mutation in FLNB. This frameshift mutation lies in the C-terminal-most domain involved in FLNB dimerization and resulted in a 20-residue elongation, with complete familial segregation and absence in 376 normal controls. The mutant p.S2542Lfs*82 FLNB demonstrated a complete loss of ability to form a functional dimer in transiently transfected HEK293T cells. The p.S2542Lfs*82 mutation also led to significantly reduced protein levels and accumulation of the mutant protein in the Golgi apparatus. This is the first identified mutation in the dimerization domain of FLNB. This loss-of-function frameshift mutation in FLNB causes autosomal-recessive SCT with rarely reported rib anomalies. This report demonstrates the involvement of rib anomaly in SCT and its causative mutation in the dimerization domain of FLNB.
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Chi-Fan
authors.initials: CF
authors.lastname: Yang
authors.affiliation: Department of Genetics and Metabolism, Children's Hospital of China Medical University, Taichung, Taiwan.|School of Medicine, China Medical University, Taichung, Taiwan.
authors.forename: Chung-Hsing
authors.initials: CH
authors.lastname: Wang
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Weng
authors.initials: W
authors.lastname: Siong H'ng
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Chun-Ping
authors.initials: CP
authors.lastname: Chang
authors.affiliation: Department of Medical Genetics, China Medical University Hospital, Taichung, Taiwan.|School of Post Baccalaureate Chinese Medicine, China Medical University, Taichung, Taiwan.
authors.forename: Wei-De
authors.initials: WD
authors.lastname: Lin
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Yuan-Tsong
authors.initials: YT
authors.lastname: Chen
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Jer-Yuarn
authors.initials: JY
authors.lastname: Wu
authors.affiliation: Department of Medical Genetics, China Medical University Hospital, Taichung, Taiwan.|Department of Medical Research, China Medical University Hospital, Taichung, Taiwan.|School of Chinese Medicine, China Medical University, Taichung, Taiwan.|Division of Pediatric Genetics, Endocrinology & Metabolism, China Medical University Children's Hospital, Taichung, Taiwan.
authors.forename: Fuu-Jen
authors.initials: FJ
authors.lastname: Tsai
mesh_terms: D000015:Abnormalities, Multiple / Q000175:diagnosis* / Q000235:genetics*; D000199:Actins / Q000378:metabolism; D000328:Adult; D019943:Amino Acid Substitution; D004252:DNA Mutational Analysis; D005260:Female; D064448:Filamins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D005808:Genes, Recessive; D006056:Golgi Apparatus / Q000378:metabolism; D006720:Homozygote; D006801:Humans; D008159:Lumbar Vertebrae / Q000002:abnormalities*; D009140:Musculoskeletal Diseases / Q000175:diagnosis* / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D054730:Protein Interaction Domains and Motifs / Q000235:genetics*; D055503:Protein Multimerization / Q000235:genetics*; D055550:Protein Stability; D012600:Scoliosis / Q000151:congenital* / Q000175:diagnosis / Q000235:genetics; D013580:Synostosis / Q000175:diagnosis* / Q000235:genetics*; D013904:Thoracic Vertebrae / Q000002:abnormalities*; D014057:Tomography, X-Ray Computed; D055815:Young Adult
chemical_list: D000199:Actins; D064448:Filamins
keywords: FLNB; SCT; filamin B; loss-of-function; spondylocarpotarsal synostosis syndrome