BGN Mutations in X-Linked Spondyloepimetaphyseal Dysplasia

  • Am J Hum Genet. 2016 Jun 2;98(6):1243-1248. doi: 10.1016/j.ajhg.2016.04.004.
Sung Yoon Cho  1 ,  Jun-Seok Bae  2 ,  Nayoung K D Kim  3 ,  Francesca Forzano  4 ,  Katta Mohan Girisha  5 ,  Chiara Baldo  6 ,  Francesca Faravelli  4 ,  Tae-Joon Cho  7 ,  Dongsup Kim  8 ,  Kyoung Yeul Lee  8 ,  Shiro Ikegawa  9 ,  Jong Sup Shim  10 ,  Ah-Ra Ko  11 ,  Noriko Miyake  12 ,  Gen Nishimura  13 ,  Andrea Superti-Furga  14 ,  Jürgen Spranger  15 ,  Ok-Hwa Kim  16 ,  Woong-Yang Park  17 ,  Dong-Kyu Jin  18
Affiliations
  • 1. Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea.
  • 2. Samsung Genome Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea; Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea.
  • 3. Samsung Genome Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea.
  • 4. Division of Medical Genetics, Galliera Hospital, Via Volta 6, Genova 16128, Italy.
  • 5. Department of Medical Genetics, Kasturba Medical College, Manipal University, Manipal 576104, India.
  • 6. Laboratory of Human Genetics, Galliera Hospital, Genova 16128, Italy.
  • 7. Division of Pediatric Orthopaedics, Seoul National University Children's Hospital, Seoul 03080, Republic of Korea.
  • 8. Department of Systems Biology, Korea Advanced Institute of Science and Technology, Daejon 34141, Republic of Korea.
  • 9. Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo 108-8639, Japan.
  • 10. Department of Orthopedic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea.
  • 11. Clinical Research Center, Samsung Biomedical Research Center, Seoul 06351, Republic of Korea.
  • 12. Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
  • 13. Department of Pediatric Imaging, Tokyo Metropolitan Children's Medical Center, Fuchu 183-8561, Japan.
  • 14. Department of Pediatrics, Centre Hospitalier Universitaire Vaudois, University of Lausanne (CHUV), Lausanne 1011, Switzerland.
  • 15. Im Fuchsberg 14, 76547 Sinzheim, Germany.
  • 16. Department of Radiology, Woorisoa Children's Hospital, Seoul 08291, Republic of Korea.
  • 17. Samsung Genome Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea; Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea; Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon 16419, Republic of Korea. Electronic address: [email protected].
  • 18. Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea. Electronic address: [email protected].
PMID: 27236923 DOI: 10.1016/j.ajhg.2016.04.004
Abstract

Spondyloepimetaphyseal dysplasias (SEMDs) comprise a heterogeneous group of autosomal-dominant and autosomal-recessive disorders. An apparent X-linked recessive (XLR) form of SEMD in a single Italian family was previously reported. We have been able to restudy this family together with a second family from Korea by segregating a severe SEMD in an X-linked pattern. Exome Sequencing showed missense mutations in BGN c.439A>G (p.Lys147Glu) in the Korean family and c.776G>T (p.Gly259Val) in the Italian family; the c.439A>G (p.Lys147Glu) mutation was also identified in a further simplex SEMD case from India. Biglycan is an extracellular matrix proteoglycan that can bind transforming growth factor beta (TGF-β) and thus regulate its free concentration. In 3-dimensional simulation, both altered residues localized to the concave arc of leucine-rich repeat domains of biglycan that interact with TGF-β. The observation of recurrent BGN mutations in XLR SEMD individuals from different ethnic backgrounds allows us to define "XLR SEMD, BGN type" as a nosologic entity.