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Case Reports
. 2017 Feb 2;100(2):364-370.
doi: 10.1016/j.ajhg.2017.01.014.

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

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
Case Reports

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

John Y W Lee et al. Am J Hum Genet. .

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.

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Figures

Figure 1
Figure 1
Pedigree and Molecular Pathology of SPG23 (A) The family pedigree of family 1. Squares denote male family members and circles female family members; filled-in symbols indicate clinically affected individuals. The triangle (IV-2) refers to a spontaneous abortion. (B) Affected individual IV-5 with gray/white hair in the scalp and eyebrows and dyspigmentation on the forehead. (C) Similar changes affecting hair follicle pigmentation are present in the beard area (individual IV-5). (D) Blotchy dyspigmentation, hypopigmentation, and depigmentation on the dorsum of the hands with marked pigment loss and some erythema around the finger nails. (E) Loss of skin pigment (vitiligo-like lesions) on the flexural aspects of the wrists and forearms (individual IV-5). (F) Integrative Genomics Viewer analysis reveals homozygous loss of exons 12 and 13 and part of the 3′ UTR of DSTYK in affected individuals IV-5, IV-8, VI-1, and VI-2. Heterozygous changes are implicated in the parental samples (III-3, III-4, V-1, and V-2). (G) Schematic of DSTYK to show the homozygous mutation and Sanger sequencing confirmation of the 4-kb deletion/20-bp insertion in genomic DNA (affected individual IV-5). The schematic also illustrates the previous mutations in DSTYK identified in a different disorder, autosomal-dominant congenital anomalies of the kidney and urinary tract-1 (CAKUT1).
Figure 2
Figure 2
Skin Pathology in SPG23 (A) Immunofluorescence microscopy using a DSTYK N-terminal antibody (NBP1-92336, 1:500, Novus Biologicals) in normal skin (top) reveals bright pan-epidermal cytoplasmic staining with focal accentuation in basal epidermal melanocytes and dermal fibroblasts. In affected individual (IV-5) skin (middle), there is markedly reduced labeling, with an absence of staining in the negative control (bottom) (scale bar represents 100 μm). (B) Immunofluorescence microscopy using a DSTYK C-terminal antibody (1:500, Santa Cruz Biotechnology cat# sc-374487, RRID: AB_10988978) in normal skin (top) reveals bright pan-epidermal cytoplasmic staining with focal accentuation in basal epidermal melanocytes and dermal fibroblasts. In affected individual (IV-5) skin (middle) there is markedly reduced labeling, with an absence of staining in the negative control (bottom). (C) Transmission electron micrograph of a melanocyte (affected individual IV-5) shows prominent mitochondria and abnormal cytoplasmic vacuoles (asterisk) (scale bar represents 2 μm). (D) Transmission electron micrograph of a keratinocyte (affected individual IV-5) shows prominent swollen mitochondria with abnormal cristae (asterisks) (scale bar represents 2 μm).
Figure 3
Figure 3
Increased Sensitivity to Apoptosis in DSTYK-Null Cells (A) Western blots of DSTYK protein levels in mouse NIH 3T3 fibroblasts transfected with non-targeting siRNA (control) or siRNA pool specifically targeted to Dstyk (Dstyksi). Graph shows percentage of total starting cells attached 9 hr after UV illumination. Values are means ± standard error of the mean (SEM). Representative of three independent experiments. ∗p < 0.05. (B) Western blots of DSTYK protein levels in human fibroblasts isolated from healthy donors (control) or affected individual (IV-5). Graph shows percentage of total starting cells attached 9 hr after UV illumination. Values are means ± SEM. Representative of three independent experiments. ∗p < 0.05. (C) Western blots of DSTYK protein levels in mouse keratinocytes transfected with non-targeting siRNA (control) or siRNA pool specifically targeted to Dstyk (Dstyksi). Graph shows percentage of total starting cells attached 9 hr after UV illumination. Values are means ± SEM. Representative of three independent experiments. ∗p < 0.05. (D) Western blots of DSTYK protein levels in human keratinocytes isolated from healthy donors (control) or affected individual (IV-5). Graph shows percentage of total starting cells attached 9 hr after UV illumination. Values are means ± SEM. Representative of three independent experiments. ∗p < 0.05. (E) Western blots of DSTYK protein levels in mouse melanocytes transfected with non-targeting siRNA (control) or siRNA pool specifically targeted to Dstyk (Dstyksi). Graph shows percentage of total starting cells attached 9 hr after UV illumination. Values are means ± SEM. Representative of three independent experiments. ∗p < 0.05.
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