Large Intragenic Deletion in DSTYK Underlies Autosomal-Recessive Complicated Spastic Paraparesis, SPG23

  • Am J Hum Genet. 2017 Feb 2;100(2):364-370. doi: 10.1016/j.ajhg.2017.01.014.
John Y W Lee  1 ,  Chao-Kai Hsu  2 ,  Magdalene Michael  3 ,  Arti Nanda  4 ,  Lu Liu  5 ,  James R McMillan  5 ,  Celine Pourreyron  6 ,  Takuya Takeichi  7 ,  Jakub Tolar  8 ,  Evan Reid  9 ,  Thomas Hayday  3 ,  Sergiu C Blumen  10 ,  Saif Abu-Mouch  11 ,  Rachel Straussberg  12 ,  Lina Basel-Vanagaite  13 ,  Yael Barhum  14 ,  Yasmin Zouabi  15 ,  Hejab Al-Ajmi  4 ,  Hsin-Yu Huang  16 ,  Ting-Chien Lin  16 ,  Masashi Akiyama  17 ,  Julia Y Y Lee  16 ,  W H Irwin McLean  18 ,  Michael A Simpson  19 ,  Maddy Parsons  3 ,  John A McGrath  20
Affiliations
  • 1. St John's Institute of Dermatology, King's College London (Guy's Campus), London SE1 9RT, UK.
  • 2. Department of Dermatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan; Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.
  • 3. Randall Division of Cell and Molecular Biophysics, King's College London (Guy's Campus), London SE1 9RT, UK.
  • 4. As'ad Al-Hamad Dermatology Center, Al-Sabah Hospital, Kuwait City 13001, Kuwait.
  • 5. The National Diagnostic EB Laboratory, Viapath, St Thomas' Hospital, London SE1 7EH, UK.
  • 6. Jacqui Wood Cancer Centre, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.
  • 7. St John's Institute of Dermatology, King's College London (Guy's Campus), London SE1 9RT, UK; Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan.
  • 8. Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN 55455, USA; Stem Cell Institute, University of Minnesota, Minneapolis, MN 55455, USA.
  • 9. Cambridge Institute for Medical Research (CIMR), University of Cambridge, Cambridge CB2 0XY, UK; Department of Medical Genetics, Addenbrooke's Hospital, University of Cambridge, Cambridge CB2 0QQ, UK.
  • 10. Department of Neurology, Hillel Yaffe Medical Center, Hadera 38100, Israel; Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa 3525433, Israel.
  • 11. Liver Unit, Department of Internal Medicine B, Hillel Yaffe Medical Center, Hadera 38100, Israel.
  • 12. Neurogenetic Service, Neurology Institute, Schneider Children's Medical Center, Petah Tikva 49202, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
  • 13. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; Raphael Recanati Genetic Institute, Rabin Medical Center, Beilinson Campus, Petah Tikva 49100, Israel; Pediatric Genetics Unit, Schneider Children's Medical Center, Petah Tikva 49202, Israel; Felsenstein Medical Research Center, Rabin Medical Center, Petah Tikva 4941492, Israel.
  • 14. Laboratory of Clinical Neuroscience, Felsenstein Medical Research Center, Rabin Medical Center, Petah Tikva 4941492, Israel; Department of Neurology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
  • 15. Neurogenetic Service, Neurology Institute, Schneider Children's Medical Center, Petah Tikva 49202, Israel.
  • 16. Department of Dermatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.
  • 17. Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan.
  • 18. Centre for Dermatology and Genetic Medicine, Division of Molecular Medicine, University of Dundee, Dundee DD1 5EH, UK.
  • 19. Department of Medical and Molecular Genetics, King's College London, School of Medicine, Guy's Hospital, London SE1 9RT, UK.
  • 20. St John's Institute of Dermatology, King's College London (Guy's Campus), London SE1 9RT, UK; Centre for Dermatology and Genetic Medicine, Division of Molecular Medicine, University of Dundee, Dundee DD1 5EH, UK. Electronic address: [email protected].
PMID: 28157540 DOI: 10.1016/j.ajhg.2017.01.014
Abstract

SPG23 is an autosomal-recessive neurodegenerative subtype of lower limb spastic paraparesis with additional diffuse skin and hair dyspigmentation at birth followed by further patchy pigment loss during childhood. Previously, genome-wide linkage in an Arab-Israeli pedigree mapped the gene to an approximately 25 cM locus on chromosome 1q24-q32. By using whole-exome Sequencing in a further Palestinian-Jordanian SPG23 pedigree, we identified a complex homozygous 4-kb deletion/20-bp insertion in DSTYK (dual serine-threonine and tyrosine protein kinase) in all four affected family members. DSTYK is located within the established linkage region and we also found the same mutation in the previously reported pedigree and another Israeli pedigree (total of ten affected individuals from three different families). The mutation removes the last two exons and part of the 3' UTR of DSTYK. Skin biopsies revealed reduced DSTYK protein levels along with focal loss of melanocytes. Ultrastructurally, swollen mitochondria and cytoplasmic vacuoles were also noted in remaining melanocytes and some keratinocytes and fibroblasts. Cultured keratinocytes and fibroblasts from an affected individual, as well as knockdown of Dstyk in mouse melanocytes, keratinocytes, and fibroblasts, were associated with increased cell death after ultraviolet irradiation. Keratinocytes from an affected individual showed loss of kinase activity upon stimulation with Fibroblast Growth Factor. Previously, dominant mutations in DSTYK were implicated in congenital urological developmental disorders, but our study identifies different phenotypic consequences for a recurrent autosomal-recessive deletion mutation in revealing the genetic basis of SPG23.

Keywords
DSTYK; Spastic Paraplegia 23; autosomal-recessive; deletion; gene; hereditary spastic paraplegia; mutation; pigmentation; vitiligo; whole-exome sequencing.