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.The Centre for Dermatology and Genetic Medicine is supported by a Wellcome Trust Strategic Award (reference 098439/Z/12/Z). The work was supported by the MRC (MR/M018512/1) and the UK National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre (BRC) award to Guy’s and St. Thomas’ NHS Foundation Trust, in partnership with the King’s College London and King’s College Hospital NHS Foundation Trust. This study was also supported by UK Medical Research Council Project Grant (MR/M00046X/1) and Action Research grant SP3706 as well as medical student grants from the Jean Shanks Foundation and the British Association of Dermatologists

Is there a circadian rhythm of postural control and perception of the vertical?

International audienceDaytime activity is largely regulated by the day/night pattern. Various physiological and cognitive functions display a variation during the diurnal period, where individuals manage their balance, spatial orientation and consequently their perception of the vertical. However, findings concerning daytime changes of postural control quality remain contradictory, mainly due to methodogical considerations. The aim of our study is to evaluate the effect of time of day on postural control and perception of the vertical. Fifteen male subjects underwent six test sessions over a 24-hour period. Each session involved a postural balance test (static/dynamic; eyes open/closed) and a subjective evaluation of sleepiness, fatigue and subjective visual vertical (SVV) (light stick tilted from 10 to 40°; eight trials). No time-of-day effect was observed on postural balance. However, perception of the vertical fluctuates during the day and is better at 10 a.m. than at 10 p.m. Despite the gradual perception of the vertical deterioration over the day, postural balance does not show any fluctuation. This postural balance consistency throughout the day may be the result of compensation mechanisms