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

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.

Dstyk mutation leads to congenital scoliosis-like vertebral malformations in zebrafish via dysregulated mTORC1/TFEB pathway

“…More importantly, the incidence of scoliosis is inconsistent in different species. While we found all dstyk mutant zebrafishes have severe scoliosis, among the seven SPG23 families with mutation of DSTYK reported, only patients in three families have scoliosis 58 . These studies indicate that DSTYK mutation may lead to scoliosis in human, but we currently do not know whether the scoliosis in those patients with DSTYK mutation is related to the direct effect of DSTYK mutation on spine development or secondary to the spastic paraparesis.…”

“…Previous studies reported that patients with a large intragenic deletion of DSTYK as the genetic basis for Spastic Paraparesis type 23 (SPG23), an autosomal-recessive disorder characterized by progressive spastic paraplegia and skin pigment abnormalities 58 . In fact, melanosomes in skin and hair melanocytes also belong to LROs, and disordered melanosome biogenesis has been found to result in pigment abnormalities 38 .…”

“…One intriguing phenomena about the role of DSTYK in the development and homeostasis is the variable phenotypes among Dstyk deficient zebrafishes, mice and humans. Patients with heterozygous mutations of DSTYK were identified as a frequent cause of autosomal-dominant congenital anomalies of the kidney and urinary tract-1 (CAKUT1), and homozygous mutations were identified as SPG23 40,58 , suggesting the essential role of DSTYK in the human development. Li et al however, reported that mice with ablation of Dstyk kinase domain showed no obvious developmental defects 61 .…”

Novel homozygous missense mutation in NT5C2 underlying hereditary spastic paraplegia SPG45

“…We performed exome sequencing in nine individuals from this pedigree (Figure a), two of whom are affected (IV:8 and IV:10). Variant calling was performed with a previously published in‐house pipeline (Lee et al, ). More than 4.9 Gb of sequence was generated per sample, such that >94% of the target exome was present at >20‐fold coverage, and >98% was present at fivefold coverage (Supplementary Tables S1 and S2).…”

Genetic basis of human congenital anomalies of the kidney and urinary tract

“…A number of mutation carriers also manifested neurologic phenotypes such as ataxia and epilepsy, suggesting that DSTYK mutation can affect neurologic development (110). It is thus interesting that a recent study reported homozygosity for a rare intragenic deletion that encompasses the last two exons and the 3′ UTR of DSTYK in three unrelated families of Middle-Eastern ancestry with autosomal recessive spastic paraparesis (111). The proband phenotype in one family also included a horseshoe kidney, suggesting that this particular DSTYK mutation can also affect kidney and urinary tract development.…”