Candidate gene study of HOXB1 in autism spectrum disorder.
Candidate gene study of HOXB1 in autism spectrum disorder.
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DOI：
10.1186/2040-2392-1-9
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发表时间：
2010-05-25
期刊：
影响因子：
6.2
通讯作者：
Persico AM
中科院分区：
文献类型：
--
作者：
Muscarella LA;Guarnieri V;Sacco R;Curatolo P;Manzi B;Alessandrelli R;Giana G;Militerni R;Bravaccio C;Lenti C;Saccani M;Schneider C;Melmed R;D'Agruma L;Persico AM
HOXB1 在脑干形态发生中起着重要作用，并且可以与 HOXA1 一起部分决定颅周。在我们的样本中，HOXA1 等位基因显着影响自闭症患者和人群对照的头部生长率。一份初步报告表明 HOXB1 与 HOXA1 相互作用可能会导致自闭症易感性，但该报告并未得到五项小型关联研究的证实。我们的样本包括 269 名自闭症患者，属于 219 个单一家庭和 28 个多重家庭。通过变性高效液相色谱，然后进行 DNA 测序，对 84 名自闭症患者的 HOXB1 基因的两个外显子和侧翼内含子序列进行了突变分析。然后通过限制性分析在 236 名自闭症患者和 325-345 名对照者中搜索已识别的罕见变异。对 169 名意大利患者、184 名意大利对照者以及 247 名三人组的两种常见变异进行了病例对照和基于家庭的关联研究。我们鉴定了三种常见的多态性，rs72338773 [c.82insACAGCGCCC (INS/nINS)]、rs12939811 [c.309A>T (Q103H)] 和 rs7207109 [c.450G>A (A150A)] 和三种罕见的变异，即 IVS1+63G>A， rs35115415 [c.702G>A (V234V)] 和 c.872_873delinsAA (S291N)。使用病例对照（等位基因，精确 P = 0.13）或基于家族的设计 [传输/不平衡检验 (TDT)χ2 = 1.774，P = 0.183]，SNP rs72338773 和 rs12939811 与自闭症无关。这些罕见的变异均遗传自其中一位父母，存在于两个意大利家庭和两个白人美国家庭中。两个家庭中的自闭症先证者令人惊讶地从父母那里继承了一种独特的罕见变异。 IVS1+63A 等位基因存在于 3/690 对照染色体中，而 rs35115415 和 c.872_873delinsAA (S291N) 处的罕见等位基因分别在 662 和 650 对照染色体中未发现。 INS-T309 等位基因影响头部大小，但其影响似乎更温和，并且与 HOXA1 等位基因没有相互作用。根据 ADI-R 评分，INS-T309 等位基因还与更严重的刻板行为相关（N = 60 名患者，P < 0.01）。 HOXB1 突变并不代表自闭症的常见原因，HOXB1 常见变异在自闭症脆弱性中也不发挥重要作用。 HOXB1 对自闭症患者的头围贡献虽小，但可检测到，而 HOXA1 则表现出更显着的影响。 HOXB1 变异可能会调节临床表型，特别是在刻板行为领域。
HOXB1 plays a major role in brainstem morphogenesis and could partly determine the cranial circumference in conjunction with HOXA1. In our sample, HOXA1 alleles significantly influence head growth rates both in autistic patients and in population controls. An initial report, suggesting that HOXB1 could confer autism vulnerability in interaction with HOXA1, was not confirmed by five small association studies. Our sample includes 269 autistic individuals, belonging to 219 simplex and 28 multiplex families. A mutational analysis of the two exons and flanking intronic sequences of the HOXB1 gene was carried out in 84 autistic patients by denaturing high performance liquid chromatography, followed by DNA sequencing. Identified rare variants were then searched by a restriction analysis in 236 autistic patients and 325-345 controls. Case-control and family-based association studies were performed on two common variants in 169 Italian patients versus 184 Italian controls and in 247 trios. We identified three common polymorphisms, rs72338773 [c.82insACAGCGCCC (INS/nINS)], rs12939811 [c.309A>T (Q103H)], and rs7207109 [c.450G>A (A150A)] and three rare variants, namely IVS1+63G>A, rs35115415 [c.702G>A (V234V)] and c.872_873delinsAA (S291N). SNPs rs72338773 and rs12939811 were not associated with autism, using either a case-control (alleles, exact P = 0.13) or a family-based design [transmission/disequilibrium test (TDT)χ2 = 1.774, P = 0.183]. The rare variants, all inherited from one of the parents, were present in two Italian and in two Caucasian-American families. Autistic probands in two families surprisingly inherited a distinct rare variant from each parent. The IVS1+63A allele was present in 3/690 control chromosomes, whereas rare alleles at rs35115415 and c.872_873delinsAA (S291N) were not found in 662 and 650 control chromosomes, respectively. The INS-T309 allele influenced head size, but its effect appears more modest and shows no interaction with HOXA1 alleles. The INS-T309 allele is also associated with more severe stereotypic behaviours, according to ADI-R scores (N = 60 patients, P < 0.01). HOXB1 mutations do not represent a common cause of autism, nor do HOXB1 common variants play important roles in autism vulnerability. HOXB1 provides minor, albeit detectable contributions to head circumference in autistic patients, with HOXA1 displaying more prominent effects. HOXB1 variants may modulate the clinical phenotype, especially in the area of stereotypic behaviours.
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影响因子：
14.5
作者：
Bailey, A;Luthert, P;Lantos, P
通讯作者：
Lantos, P
影响因子：
6.9
作者：
BAILEY, A;LECOUTEUR, A;RUTTER, M
通讯作者：
RUTTER, M
DOI：
10.1002/ajmg.b.20094
发表时间：
2004-01-01
影响因子：
2.8
作者：
Gallagher, L;Hawi, Z;Gill, M
通讯作者：
Gill, M
影响因子：
4
作者：
Jacquemont ML;Sanlaville D;Redon R;Raoul O;Cormier-Daire V;Lyonnet S;Amiel J;Le Merrer M;Heron D;de Blois MC;Prieur M;Vekemans M;Carter NP;Munnich A;Colleaux L;Philippe A
通讯作者：
Philippe A
影响因子：
64.8
作者：
Glessner, Joseph T.;Wang, Kai;Cai, Guiqing;Korvatska, Olena;Kim, Cecilia E.;Wood, Shawn;Zhang, Haitao;Estes, Annette;Brune, Camille W.;Bradfield, Jonathan P.;Imielinski, Marcin;Frackelton, Edward C.;Reichert, Jennifer;Crawford, Emily L.;Munson, Jeffrey;Sleiman, Patrick M. A.;Chiavacci, Rosetta;Annaiah, Kiran;Thomas, Kelly;Hou, Cuiping;Glaberson, Wendy;Flory, James;Otieno, Frederick;Garris, Maria;Soorya, Latha;Klei, Lambertus;Piven, Joseph;Meyer, Kacie J.;Anagnostou, Evdokia;Sakurai, Takeshi;Game, Rachel M.;Rudd, Danielle S.;Zurawiecki, Danielle;McDougle, Christopher J.;Davis, Lea K.;Miller, Judith;Posey, David J.;Michaels, Shana;Kolevzon, Alexander;Silverman, Jeremy M.;Bernier, Raphael;Levy, Susan E.;Schultz, Robert T.;Dawson, Geraldine;Owley, Thomas;McMahon, William M.;Wassink, Thomas H.;Sweeney, John A.;Nurnberger, John I., Jr.;Coon, Hilary;Sutcliffe, James S.;Minshew, Nancy J.;Grant, Struan F. A.;Bucan, Maja;Cook, Edwin H., Jr.;Buxbaum, Joseph D.;Devlin, Bernie;Schellenberg, Gerard D.;Hakonarson, Hakon
通讯作者：
Hakonarson, Hakon