Exome Sequencing Reveals a Homozygous SYT14 Mutation in Adult-Onset, Autosomal-Recessive Spinocerebellar Ataxia with Psychomotor Retardation

Autosomal-recessive cerebellar ataxias (ARCAs) are clinically and genetically heterogeneous disorders associated with diverse neurological and nonneurological features that occur before the age of 20. Currently, mutations in more than 20 genes have been identified, but approximately half of the ARCA patients remain genetically unresolved. In this report, we describe a Japanese family in which two siblings have slow progression of a type of ARCA with psychomotor retardation. Using whole-exome sequencing combined with homozygosity mapping, we identified a homozygous missense mutation in SYT14, encoding synaptotagmin XIV (SYT14). Expression analysis of the mRNA of SYT14 by a TaqMan assay confirmed that SYT14 mRNA was highly expressed in human fetal and adult brain tissue as well as in the mouse brain (especially in the cerebellum). In an in vitro overexpression system, the mutant SYT14 showed intracellular localization different from that of the wild-type. An immunohistochemical analysis clearly showed that SYT14 is specifically localized to Purkinje cells of the cerebellum in humans and mice. Synaptotagmins are associated with exocytosis of secretory vesicles (including synaptic vesicles), indicating that the alteration of the membrane-trafficking machinery by the SYT14 mutation may represent a distinct pathomechanism associated with human neurodegenerative disorders

ミトコンドリア脳筋症における少量ジクロロ酢酸療法の臨床的評価 : ジクロロ酢酸少量内服療法が卒中様発作抑制に有効であった5症例について

筋生検・ミトコンドリアDNA遺伝子診断などによりMELASと診断され,脳卒中様発作を繰り返し,頭部MRIで病変が確認された成人MELAS5症例に,少量のジクロロ酢酸を含むLiverall^を投与し,脳卒中様発作を抑制できるか臨床経過を検討した.内服開始後は,全例で頭部MRI画像上病変を認める脳卒中様発作は生じなかった.従来小児科領域で報告されていた必要量よりも少量で発作を抑制できる可能性があると考えられた.しかし,血清中の乳酸・ピルビン酸は異常値を示す場合もあり,痙攣発作やイレウスなどの合併症状を呈する症例も2例あり,今後の検討が必要と考えられた.本論文の要旨は,第44回日本神経学会総会(横浜,2003年5月)において発表した.In five adult patients with MELAS, we evaluated clinical symptoms, FLAIR and DWI brain MRI, and serum level of lactate and pyruvic acid, to assess whether stroke-like episodes in MELAS are suppressed by small dose of dichloroacetate. After beginning oral therapy of Liverall^ for MELAS, none of the five cases showed any occurrence of the stroke-like episodes associated with brain MRI lesions. We noticed that the stroke-like episodes were suppressed by using a smaller dose of dichloroacetate, compared with the dose required for therapy of pediatric patients with MELAS. In spite of favorable effect of Liverall^ for MELAS in symptomatic and MRI evaluations, the serum level of lactate and pyruvic acid continued to show abnormal values and convulsive seizures or ileus occurred in a few cases. Further investigations are required to know whether Liverall^ is a useful therapeutic drug

Autophagy-mediated regulation of phytohormone metabolism during rice anther development

<p>Autophagy has recently been shown to be required for postmeiotic anther development including anther dehiscence, programmed cell death-mediated degradation of the tapetum and pollen maturation in rice. Several phytohormones are known to play essential roles during male reproductive development including pollen maturation. However, the relationship between phytohormone metabolism and autophagy in plant reproductive development is unknown. We here comprehensively analyzed the effect of autophagy disruption on phytohormone contents in rice anthers at the flowering stage, and found that endogenous levels of active-forms of gibberellins (GAs) and cytokinin, trans-zeatin, were significantly lower in the autophagy-defective mutant, Os<i>atg7–1</i>, than in the wild type. Treatment with GA₄ partially recovered maturation of the mutant pollens, but did not recover the limited anther dehiscence as well as sterility phenotype. These results suggest that autophagy affects metabolism and endogenous levels of GAs and cytokinin in rice anthers. Reduction in bioactive GAs in the autophagy-deficient mutant may partially explain the defects in pollen maturation of the autophagy-deficient mutant, but tapetal autophagy also plays other specific roles in fertilization.</p