Large Intragenic Deletion in DSTYK Underlies Autosomal-Recessive Complicated Spastic Paraparesis, SPG23.
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.
St John's Institute of Dermatology, King's College London (Guy's Campus), London SE1 9RT, UK.
John Y W
JYW
Lee
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.
Chao-Kai
CK
Hsu
Randall Division of Cell and Molecular Biophysics, King's College London (Guy's Campus), London SE1 9RT, UK.
Magdalene
M
Michael
As'ad Al-Hamad Dermatology Center, Al-Sabah Hospital, Kuwait City 13001, Kuwait.
Arti
A
Nanda
The National Diagnostic EB Laboratory, Viapath, St Thomas' Hospital, London SE1 7EH, UK.
Lu
L
Liu
The National Diagnostic EB Laboratory, Viapath, St Thomas' Hospital, London SE1 7EH, UK.
James R
JR
McMillan
Jacqui Wood Cancer Centre, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.
Celine
C
Pourreyron
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.
Takuya
T
Takeichi
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.
Jakub
J
Tolar
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.
Evan
E
Reid
Randall Division of Cell and Molecular Biophysics, King's College London (Guy's Campus), London SE1 9RT, UK.
Thomas
T
Hayday
Department of Neurology, Hillel Yaffe Medical Center, Hadera 38100, Israel; Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa 3525433, Israel.
Sergiu C
SC
Blumen
Liver Unit, Department of Internal Medicine B, Hillel Yaffe Medical Center, Hadera 38100, Israel.
Saif
S
Abu-Mouch
Neurogenetic Service, Neurology Institute, Schneider Children's Medical Center, Petah Tikva 49202, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
Rachel
R
Straussberg
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.
Lina
L
Basel-Vanagaite
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.
Yael
Y
Barhum
Neurogenetic Service, Neurology Institute, Schneider Children's Medical Center, Petah Tikva 49202, Israel.
Yasmin
Y
Zouabi
As'ad Al-Hamad Dermatology Center, Al-Sabah Hospital, Kuwait City 13001, Kuwait.
Hejab
H
Al-Ajmi
Department of Dermatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.
Hsin-Yu
HY
Huang
Department of Dermatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.
Ting-Chien
TC
Lin
Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan.
Masashi
M
Akiyama
Department of Dermatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.
Julia Y Y
JYY
Lee
Centre for Dermatology and Genetic Medicine, Division of Molecular Medicine, University of Dundee, Dundee DD1 5EH, UK.
W H Irwin
WHI
McLean
Department of Medical and Molecular Genetics, King's College London, School of Medicine, Guy's Hospital, London SE1 9RT, UK.
Michael A
MA
Simpson
Randall Division of Cell and Molecular Biophysics, King's College London (Guy's Campus), London SE1 9RT, UK.
Maddy
M
Parsons
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: john.mcgrath@kcl.ac.uk.
John A
JA
McGrath
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D044466:Asian People / Q000235:genetics; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D005091:Exons; D019066:Facies; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D008040:Genetic Linkage; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D006720:Homozygote; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D008297:Male; D008544:Melanocytes / Q000166:cytology / Q000378:metabolism; D051379:Mice; D041681:NIH 3T3 Cells; D010375:Pedigree; D010859:Pigmentation Disorders / Q000175:diagnosis / Q000235:genetics*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics*; D017384:Sequence Deletion; D015419:Spastic Paraplegia, Hereditary / Q000175:diagnosis / Q000235:genetics*; D014820:Vitiligo / Q000175:diagnosis / Q000235:genetics*; D055815:Young Adult
D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C487805:DSTYK protein, human
DSTYK; Spastic Paraplegia 23; autosomal-recessive; deletion; gene; hereditary spastic paraplegia; mutation; pigmentation; vitiligo; whole-exome sequencing