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

John Y. W. Lee, Chao-Kai Hsu, Magdalene Michael, Arti Nanda, Lu Liu, James R. McMillan, Celine Pourreyron, Takuya Takeichi, Jakub Tolar, Evan Reid, Thomas Hayday, Sergiu C. Blumen, Saif Abu-Mouch, Rachel Straussberg, Lina Basel-Vanagaite, Yael Barhum, Yasmin Zouabi, Hejab Al-Ajmi, Hsin-Yu Huang, Ting-Chien LinMasashi Akiyama, Julia Y. Y. Lee, W. H. Irwin McLean, Michael A. Simpson, Maddy Parsons, John A. McGrath (Lead / Corresponding author)

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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.

Original languageEnglish
Pages (from-to)364-370
Number of pages7
JournalAmerican Journal of Human Genetics
Issue number2
Early online date2 Feb 2017
Publication statusPublished - 2 Feb 2017


  • Mutation
  • Deletion
  • Autosomal-recessive
  • Hereditary spastic paraplegia
  • Spastic Paraplegia 23
  • Gene amplification
  • Whole-exome sequencing
  • Pigmentation
  • Vitiligo


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