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Genetic association and characterization of FSTL5 in isolated clubfoot.
Khanshour, Anas M; Kidane, Yared H; Kozlitina, Julia; Cornelia, Reuel; Rafipay, Alexandra; De Mello, Vanessa; Weston, Mitchell; Paria, Nandina; Khalid, Aysha; Hecht, Jacqueline T; Dobbs, Matthew B; Richards, B Stephens; Vargesson, Neil; Hamra, F Kent; Wilson, Megan; Wise, Carol; Gurnett, Christina A; Rios, Jonathan J.
Afiliación
  • Khanshour AM; Center for Pediatric Bone Biology and Translational Research, Scottish Rite for Children, Dallas, TX 75219, USA.
  • Kidane YH; Center for Pediatric Bone Biology and Translational Research, Scottish Rite for Children, Dallas, TX 75219, USA.
  • Kozlitina J; McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, TX 75390, USA.
  • Cornelia R; Center for Pediatric Bone Biology and Translational Research, Scottish Rite for Children, Dallas, TX 75219, USA.
  • Rafipay A; School of Medicine, Medical Sciences & Nutrition, Institute of Medical Sciences, University of Aberdeen, Aberdeen, AB25 2ZD, Scotland, UK.
  • De Mello V; School of Medicine, Medical Sciences & Nutrition, Institute of Medical Sciences, University of Aberdeen, Aberdeen, AB25 2ZD, Scotland, UK.
  • Weston M; Department of Anatomy, University of Otago, Dunedin 9016, New Zealand.
  • Paria N; Center for Pediatric Bone Biology and Translational Research, Scottish Rite for Children, Dallas, TX 75219, USA.
  • Khalid A; Center for Pediatric Bone Biology and Translational Research, Scottish Rite for Children, Dallas, TX 75219, USA.
  • Hecht JT; Department of Pediatrics, McGovern Medical School, University of Texas Health, Houston, TX 77030, USA.
  • Dobbs MB; Paley Orthopedic and Spine Institute, West Palm Beach, FL 33407, USA.
  • Richards BS; Department of Orthopaedics, Scottish Rite for Children, Dallas, TX 75219, USA.
  • Vargesson N; Department of Orthopaedic Surgery, UT Southwestern Medical Center, Dallas, TX 75390, USA.
  • Hamra FK; School of Medicine, Medical Sciences & Nutrition, Institute of Medical Sciences, University of Aberdeen, Aberdeen, AB25 2ZD, Scotland, UK.
  • Wilson M; Department of Obstetrics and Gynecology, Cecil H. & Ida Green Center for Reproductive Biology Sciences, UT Southwestern Medical Center, Dallas, TX 75390, USA.
  • Wise C; Department of Anatomy, University of Otago, Dunedin 9016, New Zealand.
  • Gurnett CA; Center for Pediatric Bone Biology and Translational Research, Scottish Rite for Children, Dallas, TX 75219, USA.
  • Rios JJ; McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, TX 75390, USA.
Hum Mol Genet ; 29(22): 3717-3728, 2021 01 21.
Article en En | MEDLINE | ID: mdl-33105483
Talipes equinovarus (clubfoot, TEV) is a congenital rotational foot deformity occurring in 1 per 1000 births with increased prevalence in males compared with females. The genetic etiology of isolated clubfoot (iTEV) remains unclear. Using a genome-wide association study, we identified a locus within FSTL5, encoding follistatin-like 5, significantly associated with iTEV. FSTL5 is an uncharacterized gene whose potential role in embryonic and postnatal development was previously unstudied. Utilizing multiple model systems, we found that Fstl5 was expressed during later stages of embryonic hindlimb development, and, in mice, expression was restricted to the condensing cartilage anlage destined to form the limb skeleton. In the postnatal growth plate, Fstl5 was specifically expressed in prehypertrophic chondrocytes. As Fstl5 knockout rats displayed no gross malformations, we engineered a conditional transgenic mouse line (Fstl5LSL) to overexpress Fstl5 in skeletal osteochondroprogenitors. We observed that hindlimbs were slightly shorter and that bone mineral density was reduced in adult male, but not female, Prrx1-cre;Fstl5LSL mice compared with control. No overt clubfoot-like deformity was observed in Prrx1-cre;Fstl5LSL mice, suggesting FSTL5 may function in other cell types to contribute to iTEV pathogenesis. Interrogating published mouse embryonic single-cell expression data showed that Fstl5 was expressed in cell lineage subclusters whose transcriptomes were associated with neural system development. Moreover, our results suggest that lineage-specific expression of the Fstl genes correlates with their divergent roles as modulators of transforming growth factor beta and bone morphogenetic protein signaling. Results from this study associate FSTL5 with iTEV and suggest a potential sexually dimorphic role for Fstl5 in vivo.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Pie Equinovaro / Proteínas de Homeodominio / Predisposición Genética a la Enfermedad / Proteínas Relacionadas con la Folistatina Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Animals / Humans Idioma: En Revista: Hum Mol Genet Asunto de la revista: BIOLOGIA MOLECULAR / GENETICA MEDICA Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Pie Equinovaro / Proteínas de Homeodominio / Predisposición Genética a la Enfermedad / Proteínas Relacionadas con la Folistatina Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Animals / Humans Idioma: En Revista: Hum Mol Genet Asunto de la revista: BIOLOGIA MOLECULAR / GENETICA MEDICA Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido