利用者:加藤勝憲/XYLT1

An Error has occurred retrieving Wikidata item for infoboxキシロシルトランスフェラーゼ1は、ヒトではXYLT1遺伝子によってコードされている酵素である[1][2]。

Xylosyltransferase 1 is an enzyme that in humans is encoded by the XYLT1 gene.

キシロース転移酵素(XT; EC 2.4.2.26)は、標的タンパク質のXT認識配列内のセリン残基にUDP-キシロースの転移を触媒する。このキシロースのコアタンパク質への付加は、プロテオグリカンに特徴的なグリコサミノグリカン鎖の生合成に必要である[supplied by OMIM][2] 。

Xylosyltransferase (XT; EC 2.4.2.26) catalyzes the transfer of UDP-xylose to serine residues within XT recognition sequences of target proteins. Addition of this xylose to the core protein is required for the biosynthesis of the glycosaminoglycan chains characteristic of proteoglycans.[supplied by OMIM]

Clinical relevance

Baratela-Scott syndrome

2012年、Baratela-Scott症候群がヒトで同定された[3]。XYLT1のGGCリピート拡大とエクソン1のメチル化は、Baratela-Scott症候群に共通する病因変異である[4]。

In 2012 Baratela-Scott syndrome was identified in humans. A GGC repeat expansion, and methylation of exon 1 of XYLT1 is a common pathogenic variant in Baratela-Scott syndrome.

Bartarlla-Scott症候群の患者は、骨格の異常発達、特徴的な顔貌、認知発達遅滞を示す。骨格の問題としては、膝蓋の位置がずれていること、長骨が短く幅の狭い部分に軽度の変化があること、手のひらの骨が短く親指がスタブしていること、太ももの首が短いこと、股関節のソケットが浅いこと、脊椎の奇形などがある。特徴的な顔貌は、扁平な中顔面に広い鼻梁、口蓋裂、一本眉である。この症候群はまた、就学前の認知発達遅滞の発症の原因となり、注意力が低下する。認知の遅れの一部は、温厚で魅力的な性格によって覆い隠される。

Patients with Bartarlla-Scott syndrome exhibit abnormal development of the skeleton, characteristic facial features, and cognitive developmental delay. Skeletal problems include knee cap in the wrong position, short long bones with mild changes to the narrow portion, short palm bones with stub thumbs, short thigh necks, shallow hip sockets, and malformations of the spine. Characteristic facial features include a flattened midface with a broad nasal bridge, cleft palate, and unibrow. The syndrome also cause pre-school onset of a cognitive developmental delay, with a shortened attention span. Some of the cognitive delay is masked by a warm and engaging personality.

Axon extension

神経細胞は細胞外マトリックス分子の存在を、軸索の伸長を促進するか抑制するかの手がかりとしている。コンドロイチン硫酸プロテオグリカンは、脊髄の病変後に生じるバリアであるグリア瘢痕を越えて軸索が伸長するのを抑制する。プロテオグリカンは、比較的小さなタンパク質のコアと、それに結合した大きなグリコサミノグリカンの側鎖から構成されている。この側鎖の形成そのものを阻害するために、キシロースをタンパク質コアのセリンに結合させ、グリコサミノグリカン鎖の伸長を開始させるキシロシルトランスフェラーゼ（XYLT1）が、設計された一群のDNA分子によって標的とされた。これらの分子はDNA-酵素と呼ばれ、細胞内でXYLT1のmRNAを特異的に切断するように設計されている。DNA-酵素は哺乳動物細胞に容易に取り込まれるが、より安定であり、siRNAよりもはるかに低い濃度を必要とする。

Neurons use the presence of extracellular matrix molecules as clues whether to promote or suppress extension of axons. Chondroitin sulfate proteoglycans suppress the extension of axons over the glial scar, a barrier which develops after lesioning the spinal cord. Proteoglycans consist of one relatively small protein core and attached large glycosaminoglycan side chains. To block the very formation of these side chains xylosyltransferase (XYLT1) which attaches xylose to a serine of the protein core as initiation for glycosaminoglycan chain extension, was targeted by a class of designed DNA molecules. These molecules are called DNA-enzymes which were designed to specifically cleave XYLT1 mRNA within cells. DNA-enzymes are readily taken up by mammalian cells, but are more stable and require much lower concentrations then siRNA.

ニューロカンを分泌する細胞とニューロンを共培養したXTYL1 DNA-酵素は、軸索伸長の著しい増加を示した。定義された脊髄病変、すなわち臨床的に重要な挫滅損傷を有するラットに、XTYL1 DNA-酵素を微量注入ポンプまたは全身投与したところ、水平ラダー課題の改善、軸索可塑性の増強、皮質脊髄路の成長が見られた。{キシロシルトランスフェラーゼ-1 mRNAに対するデオキシリボザイムの全身投与は脊髄損傷後の回復を促進する Exp Neurol.doi: 10.1016/j.expneurol.2012.06.006.pmid: 22721770}}.

XTYL1 DNA-enzyme in co-cultures of neurons with neurocan secreting cells displayed a marked increase of axon outgrowth. Rats with defined spinal cord lesions, i.a. the clinically relevant contusion injury, treated with XTYL1 DNA-enzyme administered by micro-infusion pumps or systemically achieved improvements in the horizontal ladder task, enhanced axonal plasticity, growth of the corticospinal tract, no effect on neuropathic pain when using mechanical and thermal allodynia tests and no toxicological or pathological side effects compared to control animals.{{Oudega M, Chao OY, Avison DL, Bronson RT, Buchser WJ, Hurtado A, Grimpe B. (2012) Systemic administration of a deoxyribozyme to xylosyltransferase-1 mRNA promotes recovery after a spinal cord injury Exp Neurol. Sep;237(1):170-9. doi: 10.1016/j.expneurol.2012.06.006. PMID: 22721770}}

脚注・参考文献

 

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