CN1795386B - 孤独症的诊断 - Google Patents
孤独症的诊断 Download PDFInfo
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- CN1795386B CN1795386B CN2004800058238A CN200480005823A CN1795386B CN 1795386 B CN1795386 B CN 1795386B CN 2004800058238 A CN2004800058238 A CN 2004800058238A CN 200480005823 A CN200480005823 A CN 200480005823A CN 1795386 B CN1795386 B CN 1795386B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
- G01N33/6896—Neurological disorders, e.g. Alzheimer's disease
Abstract
本发明涉及一种诊断孤独症的方法,通过测定高浓度的某些肽的存在,分析组织标本、体液标本和/或血浆标本中是否存在某些肽,所述肽的氨基酸序列分别为SKITHRIHWESASLL、SSKITHRIHWESASLL和SSKITHRIHWESASLLR,分子量分别为1779+/-1Da、1865+/-1Da和2022+/-1Da。
Description
技术领域
本发明涉及通过对对象的标本进行简单测试而诊断孤独症的方法。
发明背景
孤独症是用于对象的综合症状的术语,意指与周围人的交流可能性差到使得该对象在其整个生命中必须由社会以不同方式照顾。
在瑞典出生的每1000人中有1-5人患有孤独症。其诊断难以确立,并可能需要数年才能获得。社会和孤独症患者的家庭必须采取的教育学和社会措施是终生的且极为昂贵。患者及其家庭的痛苦是巨大的。迄今为止还不知道任何生物化学治疗(例如使用药物)。
孤独症的病理生理学涉及神经元之间异常的通讯联系,可能与脑中异常模式肽例如神经肽有关。异常肽水平可能通过对脊髓液和/或血浆中低于10kDa的蛋白质/肽的蛋白组学研究来揭示。检测孤独症中肽异常水平将产生关于其病理生理学的新假说,并可能有助于诊断和提示新的治疗可能性。由于多数肽由较大前体分子的蛋白水解而生成,肽的异常水平可能是由异常的蛋白水解活性引起的。
关于孤独症已完成和可得到的生物化学研究非常之少,因为没有可以利用的动物模型,并且存在收集更实质性的患者材料的实际问题。
在现有技术EP-A-0 979 828中公开了一种通过测定生物液体中存在的特定肽而诊断孤独症的方法。据称包含3-4个氨基酸的所述肽当以高量存在时指示孤独症。
EP-A-0 969 015涉及诊断疾病如孤独症的方法,通过鉴定存在于组织或体液中的肽。公开的肽具有3-8个氨基酸的长度,并且分子量<1081。
Green,L.A.等人在Biological Psychiatry,50:609-613(2001)中公开,孤独症患者血浆中的催产素浓度不同于健康人。催产素-extened(OT-X)的量在孤独症患者中较高,而催产素(9个氨基酸)的量较低。
US-A-2002/0006640涉及诊断孤独症等的多肽和方法。
这些文件均未公开本发明的肽。
本发明概述
本发明基于以下假设,即孤独症的基础是脑和/或穿透或围绕脑的液体即血液和脑脊液中存在异常肽模式,这些肽中的某些可能扰乱脑用于通讯联系的信号(例如携带的神经肽)。
本发明特征在于测定存在于机体标本中的具有特定氨基酸序列的某些蛋白质/肽的存在或缺失,所述蛋白质/肽的分子量分别为1779+/-1Da,1865+/-1Da和2022+/-1Da。
具体而言,本发明涉及在组织标本、体液和/或血浆标本中测定高于正常水平的一种或多种以下的肽:
SKITHRIHWESASLL (SEQ.ID.NO.1)
SSKITHRIHWESASLL (SEQ.ID.NO.2)
SSKITHRIHWESASLLR (SEQ.ID.NO.3)
在所述方法的一个优选的实施方案中,所述肽的量大于健康对象标本中存在量的10倍。
在另一个优选的实施方案中,使用ELISA技术测定各肽。
在另一个优选的实施方案中,使用RIA技术测定各肽。
在又一个其它的优选实施方案中,使用SELDI-TOF-MS体系测定各肽。
在本发明的另一方面,其涉及用于测定所述肽的试剂盒,所述试剂盒包含对于某些肽的标志,所述肽的分子量分别为1779、1865和2022。
在其优选实施方案中,所述试剂盒包含对于一种或多种肽的标志,所述肽是由氨基酸序列SSKITHRIHWESASLLR、SSKITHRIHWESASLL和/或SKITHRIHWESASLL编码的。
体液在此是指任何体液,如血液、血清、血浆、脊髓液、脑脊液和淋巴。
以上特别鉴定的本发明的肽可以是称为补体因子C 3的血浆蛋白的片段。
本发明详述
本发明已在一项利用所谓的SELDI-TOF-MS(ClphergenBiosystems Inc.Palo Alto,CA,USA)技术-一种新的蛋白组学技术的先导研究中得到证实,通过该技术分析并比较了4名孤独症儿童和4名非孤独症儿童的血浆的肽模式。由此发现,至少3种肽,每种含有15-20个氨基酸,在所有孤独症儿童中过量表示于分子条带1700-2200道尔顿。由此在孤独症儿童血浆中所述肽的量至少10倍高于非孤独症儿童。
图1显示了获自8名个体的8幅不同的1700-2200道尔顿条带的质谱曲线图,4名无孤独症诊断,4名诊断为孤独症儿童。上面4幅为来自无孤独症诊断的个体的质谱条带,下4幅来自孤独症儿童。
很明显,在孤独症儿童的标本中有至少3个不同的峰出现,其显著区别于无孤独症诊断的儿童。当使用适宜的分子量标志时,测定到在大约1779、1865和2022道尔顿有显著的峰存在。不同的峰面积代表存在的各肽的量,所述量在来自孤独症儿童的标本中比在来自无孤独症诊断的儿童的标本中高10倍以上。
使用MS/MS质谱测定所述肽的结构,由此确定其氨基酸序列分别为SSKITHRIHWESASLLR(SEQ.ID.NO.1)、SSKITHRIHWESASLL(SEQ.ID.NO.2)和SKITHRIHWESASLL(SEQ.ID.NO.3)。第一种肽已知为补体C3f(NCBI登录号1413205A),第二种缺乏C-末端精氨酸,第三种进一步缺乏N-末端丝氨酸。
所选肽在例如血浆或脊髓液标本中的浓度可容易地通过免疫化学技术如ELISA或RIA来测定。将使用抗体,并将按照通用方案进行对抗体和/或抗原肽的标记,使用例如氯胺T法用于放射性标记。
显然,以上鉴定的这些肽在体液/组织中的高水平至少是孤独病症的标志,并可容易地用于诊断孤独症。但是,测定这些肽高水平的存在还意味着孤独症的可能发病机制已被发现,并且这可能导致对孤独症的新治疗可能性,例如通过抑制这些肽的形成。
Claims (6)
1.指示组织标本、体液标本和/或血浆标本中高浓度的某些肽的标志用于制备诊断孤独症的试剂盒的用途,所述肽的分子量分别为1779+/-1Da、1865+/-1Da和2022+/-1Da,并分别具有以下氨基酸序列
SKITHRIHWESASLL (SEQ.ID.NO.1)
SSKITHRIHWESASLL,和/或 (SEQ.ID.NO.2)
SSKITHRIHWESASLLR (SEQ.ID.NO.3)。
2.权利要求1的用途,其中孤独症对象标本中所述肽的量为非孤独症对象标本中存在量的10倍以上。
3.权利要求1-2任一项的用途,其中使用任何定量免疫化学方法。
4.权利要求1-2任一项的用途,其中使用ELISA技术测定各肽。
5.权利要求1-2任一项的用途,其中使用RIA技术测定各肽。
6.权利要求1-2任一项的用途,其中使用SELDI-TOF-MS体系测定各肽。
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE03005865 | 2003-03-04 | ||
SE0300586-5 | 2003-03-04 | ||
SE0300586A SE0300586L (sv) | 2003-03-04 | 2003-03-04 | Diagnos av autism |
PCT/SE2004/000193 WO2004079371A1 (en) | 2003-03-04 | 2004-03-02 | Diagnosis of autism |
Publications (2)
Publication Number | Publication Date |
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CN1795386A CN1795386A (zh) | 2006-06-28 |
CN1795386B true CN1795386B (zh) | 2010-08-25 |
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CN2004800058238A Expired - Fee Related CN1795386B (zh) | 2003-03-04 | 2004-03-02 | 孤独症的诊断 |
Country Status (19)
Country | Link |
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US (1) | US8268576B2 (zh) |
EP (1) | EP1608982B9 (zh) |
JP (1) | JP4452715B2 (zh) |
KR (1) | KR101096487B1 (zh) |
CN (1) | CN1795386B (zh) |
AT (1) | ATE371192T1 (zh) |
AU (1) | AU2004217571B2 (zh) |
BR (1) | BRPI0408067A (zh) |
CA (1) | CA2518066C (zh) |
DE (1) | DE602004008439T2 (zh) |
DK (1) | DK1608982T3 (zh) |
ES (1) | ES2293234T3 (zh) |
NZ (1) | NZ542149A (zh) |
PL (1) | PL1608982T3 (zh) |
PT (1) | PT1608982E (zh) |
RU (1) | RU2340900C2 (zh) |
SE (1) | SE0300586L (zh) |
WO (1) | WO2004079371A1 (zh) |
ZA (1) | ZA200507082B (zh) |
Families Citing this family (10)
Publication number | Priority date | Publication date | Assignee | Title |
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JP4677556B2 (ja) * | 2005-04-22 | 2011-04-27 | 国立大学法人 千葉大学 | 自閉症の診断薬 |
SG182971A1 (en) * | 2007-07-26 | 2012-08-30 | Phenomenome Discoveries Inc | Methods for the diagnosis, risk assessment, and monitoring of autism spectrum disorders |
WO2012082056A1 (en) | 2010-12-16 | 2012-06-21 | Autism Biodiagnosis Ltd. | Novel biomarker and uses thereof in diagnosis, treatment of autism |
WO2014018468A1 (en) | 2012-07-22 | 2014-01-30 | Indiana University Research And Technology Corporation | Modulation sapp, sapp alpha and bdnf levels in individuals diagnosed with fxs and asd |
US10634677B2 (en) | 2013-10-14 | 2020-04-28 | Indiana University Research And Technology Corporation | Use of acamprosate to modulate ERK1/2 activation in animal models for FXS and ASD and individuals diagnosed with FXS and ASD |
CN105652016A (zh) * | 2016-01-28 | 2016-06-08 | 深圳大学 | 一种孤独症检测标志物及其检测方法 |
KR102083245B1 (ko) | 2017-03-10 | 2020-03-02 | 스핑고브레인 주식회사 | 정신장애의 진단 방법 |
US11131681B2 (en) * | 2017-03-10 | 2021-09-28 | Dr. Raymond Laboratories, Inc. | Method for diagnosing psychiatric disorders |
RU2643760C1 (ru) * | 2017-08-07 | 2018-02-05 | Федеральное государственное бюджетное научное учреждение "Научный центр психического здоровья" | Способ определения необходимости использования психофармакотерапии у пациентов с расстройствами аутистического спектра на момент их обследования |
KR20190106442A (ko) | 2018-03-09 | 2019-09-18 | 스핑고브레인 주식회사 | 태지, 양수 또는 제대혈을 이용한 정신장애의 진단 방법 |
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CA2273683A1 (en) * | 1998-06-15 | 1999-12-15 | Ortho-Clinical Diagnostics, Inc. | Diagnostic markers for human disorders |
IT1303675B1 (it) * | 1998-08-04 | 2001-02-23 | Radim S P A | Metodo di determinazione di peptidi utilizzati come marker per ladiagnosi dell'autismo |
JP2003512856A (ja) | 1999-11-04 | 2003-04-08 | ヒューマン ジノーム サイエンシーズ, インコーポレイテッド | ウテログロビン様ポリヌクレオチド、ポリペプチド、および抗体 |
US6998243B2 (en) | 2001-04-30 | 2006-02-14 | Syn X Pharma, Inc. | Biopolymer marker indicative of disease state having a molecular weight of 1793 daltons |
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2003
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2004
- 2004-03-02 WO PCT/SE2004/000193 patent/WO2004079371A1/en active IP Right Grant
- 2004-03-02 EP EP04716392A patent/EP1608982B9/en not_active Expired - Lifetime
- 2004-03-02 DE DE602004008439T patent/DE602004008439T2/de not_active Expired - Lifetime
- 2004-03-02 PT PT04716392T patent/PT1608982E/pt unknown
- 2004-03-02 AU AU2004217571A patent/AU2004217571B2/en not_active Ceased
- 2004-03-02 KR KR1020057016254A patent/KR101096487B1/ko not_active IP Right Cessation
- 2004-03-02 CA CA2518066A patent/CA2518066C/en not_active Expired - Fee Related
- 2004-03-02 RU RU2005130641/15A patent/RU2340900C2/ru not_active IP Right Cessation
- 2004-03-02 AT AT04716392T patent/ATE371192T1/de active
- 2004-03-02 PL PL04716392T patent/PL1608982T3/pl unknown
- 2004-03-02 NZ NZ542149A patent/NZ542149A/en not_active IP Right Cessation
- 2004-03-02 CN CN2004800058238A patent/CN1795386B/zh not_active Expired - Fee Related
- 2004-03-02 JP JP2006507920A patent/JP4452715B2/ja not_active Expired - Fee Related
- 2004-03-02 BR BRPI0408067-0A patent/BRPI0408067A/pt not_active IP Right Cessation
- 2004-03-02 DK DK04716392T patent/DK1608982T3/da active
- 2004-03-02 ES ES04716392T patent/ES2293234T3/es not_active Expired - Lifetime
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Also Published As
Publication number | Publication date |
---|---|
NZ542149A (en) | 2008-03-28 |
WO2004079371A1 (en) | 2004-09-16 |
CA2518066A1 (en) | 2004-09-16 |
KR101096487B1 (ko) | 2011-12-20 |
CN1795386A (zh) | 2006-06-28 |
AU2004217571B2 (en) | 2009-03-12 |
RU2005130641A (ru) | 2006-02-10 |
US20120149038A1 (en) | 2012-06-14 |
RU2340900C2 (ru) | 2008-12-10 |
ZA200507082B (en) | 2007-02-28 |
AU2004217571A1 (en) | 2004-09-16 |
KR20060006774A (ko) | 2006-01-19 |
JP4452715B2 (ja) | 2010-04-21 |
EP1608982A1 (en) | 2005-12-28 |
JP2006519391A (ja) | 2006-08-24 |
SE0300586L (sv) | 2004-09-05 |
ES2293234T3 (es) | 2008-03-16 |
EP1608982B9 (en) | 2008-07-23 |
CA2518066C (en) | 2011-05-10 |
PT1608982E (pt) | 2007-11-09 |
DK1608982T3 (da) | 2007-11-26 |
SE0300586D0 (sv) | 2003-03-04 |
EP1608982B1 (en) | 2007-08-22 |
PL1608982T3 (pl) | 2008-01-31 |
DE602004008439D1 (de) | 2007-10-04 |
ATE371192T1 (de) | 2007-09-15 |
DE602004008439T2 (de) | 2008-05-21 |
US8268576B2 (en) | 2012-09-18 |
BRPI0408067A (pt) | 2006-02-14 |
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