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

详细信息    查看全文

• 作者：John Y.W. Lee¹ ; Chao-Kai Hsu² ; ³ ; ²⁵ ; Magdalene Michael⁴ ; ²⁵ ; Arti Nanda⁵ ; ²⁵ ; Lu Liu⁶ ; James R. McMillan⁶ ; Celine Pourreyron⁷ ; Takuya Takeichi¹ ; ⁸ ; Jakub Tolar⁹ ; ¹⁰ ; Evan Reid¹¹ ; ¹² ; Thomas Hayday⁴ ; Sergiu C. Blumen¹³ ; ¹⁴ ; Saif Abu-Mouch¹⁵ ; Rachel Straussberg¹⁶ ; ¹⁷ ; Lina Basel-Vanagaite¹⁷ ; ¹⁸ ; ¹⁹ ; ²⁰ ; Yael Barhum²¹ ; ²² ; Yasmin Zouabi¹⁶ ; Hejab Al-Ajmi⁵ ; Hsin-Yu Huang² ; Ting-Chien Lin² ; Masashi Akiyama⁸ ; Julia Y.Y. Lee² ; W.H. Irwin McLean²³ ; Michael A. Simpson²⁴ ; Maddy Parsons⁴ ; John A. McGrath¹ ; ²³ ; ^{john.mcgrath@kcl.ac.uk}
• 刊名：The American Journal of Human Genetics
• 出版年：2017
• 出版时间：2 February 2017
• 年：2017
• 卷：100
• 期：2
• 页码：364-370
• 全文大小：1293 K
• 卷排序：100

文摘

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.