Erin E Baschal1, Kandice Swindle1, Cristina M Justice2, Robin M Baschal3, Anoja Perera4, Cambria I Wethey1, Alex Poole1, Olivier Pourquié5, Olivier Tassy5, Nancy H Miller6. 1. Department of Orthopedics, University of Colorado Denver Anschutz Medical Campus, 13001 E 17th Place, Aurora, Colorado 80045, USA. 2. Genometrics Section, National Human Genome Research Institute, National Institutes of Health, 333 Cassell Drive, Baltimore, Maryland 21224, USA. 3. Musculoskeletal Research Center, Children's Hospital Colorado, 13123 East 16 Avenue, Aurora, Colorado, 80045. 4. Molecular Biology Facility, Stowers Institute, 1000 E. 50th Street, Kansas City, Missouri 64110, United States. 5. Department of Cell Biology and Development, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 1 rue Laurent Fries, BP 10142, 67404 Illkirch CEDEX, France. 6. Department of Orthopedics, University of Colorado Denver Anschutz Medical Campus, 13001 E 17th Place, Aurora, Colorado 80045, USA ; Musculoskeletal Research Center, Children's Hospital Colorado, 13123 East 16 Avenue, Aurora, Colorado, 80045.
Abstract
STUDY DESIGN: A hypothesis-driven study was conducted in a familial cohort to determine the potential association between variants within the TBX6 gene and Familial Idiopathic Scoliosis (FIS). OBJECTIVE: To determine if variants within exons of the TBX6 gene segregate with the FIS phenotype within a sample of families with FIS. SUMMARY OF BACKGROUND DATA: Idiopathic Scoliosis (IS) is a structural curvature of the spine whose underlying genetic etiology has not been established. IS has been reported to occur at a higher rate than expected in family members of individuals with congenital scoliosis (CS), suggesting that the two diseases might have a shared etiology. The TBX6 gene on chromosome 16p, essential to somite development, has been associated with CS in a Chinese population. Previous studies have identified linkage to this locus in families with FIS, and specifically with rs8060511, located in an intron of the TBX6 gene. METHODS: Parent-offspring trios from 11 families (13 trios, 42 individuals) with FIS were selected for Sanger sequencing of the TBX6 gene. Trios were selected from a large population of families with FIS in which a genome-wide scan had resulted in linkage to 16p. RESULTS: Sequencing analyses of the subset of families resulted in the identification of five coding variants. Three of the five variants were novel; the remaining two variants were previously characterized and account for 90% of the observed variants in these trios. In all cases, there was no correlation between transmission of the TBX6 variant allele and FIS phenotype. However, an analysis of regulatory markers in osteoblasts showed that rs8060511 is in a putative enhancer element. CONCLUSIONS: Although this study did not identify any TBX6 coding variants that segregate with FIS, we identified a variant that is located in a potential TBX6 enhancer element. Therefore, further investigation of the region is needed.
STUDY DESIGN: A hypothesis-driven study was conducted in a familial cohort to determine the potential association between variants within the TBX6 gene and Familial Idiopathic Scoliosis (FIS). OBJECTIVE: To determine if variants within exons of the TBX6 gene segregate with the FIS phenotype within a sample of families with FIS. SUMMARY OF BACKGROUND DATA: Idiopathic Scoliosis (IS) is a structural curvature of the spine whose underlying genetic etiology has not been established. IS has been reported to occur at a higher rate than expected in family members of individuals with congenital scoliosis (CS), suggesting that the two diseases might have a shared etiology. The TBX6 gene on chromosome 16p, essential to somite development, has been associated with CS in a Chinese population. Previous studies have identified linkage to this locus in families with FIS, and specifically with rs8060511, located in an intron of the TBX6 gene. METHODS: Parent-offspring trios from 11 families (13 trios, 42 individuals) with FIS were selected for Sanger sequencing of the TBX6 gene. Trios were selected from a large population of families with FIS in which a genome-wide scan had resulted in linkage to 16p. RESULTS: Sequencing analyses of the subset of families resulted in the identification of five coding variants. Three of the five variants were novel; the remaining two variants were previously characterized and account for 90% of the observed variants in these trios. In all cases, there was no correlation between transmission of the TBX6 variant allele and FIS phenotype. However, an analysis of regulatory markers in osteoblasts showed that rs8060511 is in a putative enhancer element. CONCLUSIONS: Although this study did not identify any TBX6 coding variants that segregate with FIS, we identified a variant that is located in a potential TBX6 enhancer element. Therefore, further investigation of the region is needed.
Authors: D E Comings; R Gade-Andavolu; N Gonzalez; S Wu; D Muhleman; H Blake; F Chiu; E Wang; K Farwell; S Darakjy; R Baker; G Dietz; G Saucier; J P MacMurray Journal: Clin Genet Date: 2000-07 Impact factor: 4.438
Authors: Bridget A Fernandez; Wendy Roberts; Brian Chung; Rosanna Weksberg; Stephen Meyn; Peter Szatmari; Ann M Joseph-George; Sara Mackay; Kathy Whitten; Barbara Noble; Cathy Vardy; Victoria Crosbie; Sandra Luscombe; Eva Tucker; Lesley Turner; Christian R Marshall; Stephen W Scherer Journal: J Med Genet Date: 2009-09-15 Impact factor: 6.318
Authors: Nader Ghebranious; Robert D Blank; Cathleen L Raggio; Justin Staubli; Elizabeth McPherson; Lynn Ivacic; Kristen Rasmussen; F Stig Jacobsen; Thomas Faciszewski; James K Burmester; Richard M Pauli; Oheneba Boachie-Adjei; Ingrid Glurich; Philip F Giampietro Journal: J Bone Miner Res Date: 2008-10 Impact factor: 6.741
Authors: Marwan Shinawi; Pengfei Liu; Sung-Hae L Kang; Joseph Shen; John W Belmont; Daryl A Scott; Frank J Probst; William J Craigen; Brett H Graham; Amber Pursley; Gary Clark; Jennifer Lee; Monica Proud; Amber Stocco; Diana L Rodriguez; Beth A Kozel; Steven Sparagana; Elizabeth R Roeder; Susan G McGrew; Thaddeus W Kurczynski; Leslie J Allison; Stephen Amato; Sarah Savage; Ankita Patel; Pawel Stankiewicz; Arthur L Beaudet; Sau Wai Cheung; James R Lupski Journal: J Med Genet Date: 2009-11-12 Impact factor: 6.318
Authors: Shane E McCarthy; Vladimir Makarov; George Kirov; Anjene M Addington; Jon McClellan; Seungtai Yoon; Diana O Perkins; Diane E Dickel; Mary Kusenda; Olga Krastoshevsky; Verena Krause; Ravinesh A Kumar; Detelina Grozeva; Dheeraj Malhotra; Tom Walsh; Elaine H Zackai; Paige Kaplan; Jaya Ganesh; Ian D Krantz; Nancy B Spinner; Patricia Roccanova; Abhishek Bhandari; Kevin Pavon; B Lakshmi; Anthony Leotta; Jude Kendall; Yoon-Ha Lee; Vladimir Vacic; Sydney Gary; Lilia M Iakoucheva; Timothy J Crow; Susan L Christian; Jeffrey A Lieberman; T Scott Stroup; Terho Lehtimäki; Kaija Puura; Chad Haldeman-Englert; Justin Pearl; Meredith Goodell; Virginia L Willour; Pamela Derosse; Jo Steele; Layla Kassem; Jessica Wolff; Nisha Chitkara; Francis J McMahon; Anil K Malhotra; James B Potash; Thomas G Schulze; Markus M Nöthen; Sven Cichon; Marcella Rietschel; Ellen Leibenluft; Vlad Kustanovich; Clara M Lajonchere; James S Sutcliffe; David Skuse; Michael Gill; Louise Gallagher; Nancy R Mendell; Nick Craddock; Michael J Owen; Michael C O'Donovan; Tamim H Shaikh; Ezra Susser; Lynn E Delisi; Patrick F Sullivan; Curtis K Deutsch; Judith Rapoport; Deborah L Levy; Mary-Claire King; Jonathan Sebat Journal: Nat Genet Date: 2009-10-25 Impact factor: 38.330
Authors: Donna Karolchik; Galt P Barber; Jonathan Casper; Hiram Clawson; Melissa S Cline; Mark Diekhans; Timothy R Dreszer; Pauline A Fujita; Luvina Guruvadoo; Maximilian Haeussler; Rachel A Harte; Steve Heitner; Angie S Hinrichs; Katrina Learned; Brian T Lee; Chin H Li; Brian J Raney; Brooke Rhead; Kate R Rosenbloom; Cricket A Sloan; Matthew L Speir; Ann S Zweig; David Haussler; Robert M Kuhn; W James Kent Journal: Nucleic Acids Res Date: 2013-11-21 Impact factor: 16.971
Authors: Brooke Sadler; Gabe Haller; Lilian Antunes; Xavier Bledsoe; Jose Morcuende; Philip Giampietro; Cathleen Raggio; Nancy Miller; Yared Kidane; Carol A Wise; Ina Amarillo; Nephi Walton; Mark Seeley; Darren Johnson; Conner Jenkins; Troy Jenkins; Matthew Oetjens; R Spencer Tong; Todd E Druley; Matthew B Dobbs; Christina A Gurnett Journal: J Med Genet Date: 2019-02-25 Impact factor: 6.318
Authors: Sergio De Salvatore; Laura Ruzzini; Umile Giuseppe Longo; Martina Marino; Alessandra Greco; Ilaria Piergentili; Pier Francesco Costici; Vincenzo Denaro Journal: BMC Med Genomics Date: 2022-05-19 Impact factor: 3.063
Authors: Hélène Mathieu; Shunmoogum A Patten; Jose Antonio Aragon-Martin; Louise Ocaka; Michael Simpson; Anne Child; Florina Moldovan Journal: Sci Rep Date: 2021-05-26 Impact factor: 4.379