Novel ATP13A2 (PARK9) homozygous mutation in a family with marked phenotype variability.
Novel ATP13A2 (PARK9) homozygous mutation in a family with marked phenotype variability.
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DOI：
10.1007/s10048-010-0259-0
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发表时间：
2011-02
期刊：
影响因子：
2.2
通讯作者：
Bonifati, Vincenzo
中科院分区：
文献类型：
--
作者：
Santoro, Lucio;Breedveld, Guido J.;Manganelli, Fiore;Iodice, Rosa;Pisciotta, Chiara;Nolano, Maria;Punzo, Francesca;Quarantelli, Mario;Pappata, Sabina;Di Fonzo, Alessio;Oostra, Ben A.;Bonifati, Vincenzo
ATP13A2（PARK9）和FBXO7（PARK15）基因的突变与不同形式的常染色体隐性遗传青少年发作性神经退行性疾病相关，具有重叠表型，包括左旋多巴反应性帕金森病、锥体功能障碍、认知下降和核上性凝视障碍。然而，由于所描述的患者数量较少，相关的基因型和表型的特征很差。在这里，我们报告的临床，仪器和遗传学的发现，在意大利家庭与新的PARK9和PARK15突变。先证者发展为一种严重的进行性表型，包括青少年发作的帕金森综合征、锥体功能障碍、认知能力下降和视力异常。相反，他的兄弟在31岁时的神经系统检查中仅显示出轻度异常（锥体、认知和视力）。这两个兄弟都携带一个新的纯合PARK9错义（p.G877R）和一个新的杂合PARK15突变（p.R481C）。PARK9突变取代了ATP酶活性的关键残基，因此很可能是纯合状态下的功能丧失突变和致病突变。PARK15单杂合突变的致病意义尚不清楚。在这两个同胞，DaTSCAN单光子发射计算机断层扫描显示显着的黑质纹状体多巴胺能缺陷，经颅磁刺激检测到延长的中枢运动传导时间。MRI（包括T2* 加权成像）未检测到脑铁蓄积的证据。该家族是第三个报告纯合PARK9突变的家族，第一个报告非典型青少年帕金森综合征的两个基因突变的家族，说明PARK9相关疾病可能显示广泛的家族内临床变异性和较温和的表型，表明存在强的，仍然未知的修饰剂。
Mutations in the ATP13A2 (PARK9) and FBXO7 (PARK15) genes are linked to different forms of autosomal recessive juvenile-onset neurodegenerative diseases with overlapping phenotypes, including levodopa-responsive parkinsonism, pyramidal disturbances, cognitive decline, and supranuclear gaze disturbance. However, the associated genotypes and phenotypes are poorly characterized due to the small number of patients described. Here, we report clinical, instrumental, and genetic findings in an Italian family with novel PARK9 and PARK15 mutations. The proband developed a severe progressive phenotype including juvenile-onset parkinsonism, pyramidal disturbances, cognitive decline, and oculomotor abnormalities. On the contrary, his brother only shows mild abnormalities (pyramidal, cognitive, and oculomotor) on the neurological examination at the age of 31 years. These two brothers both carry a novel homozygous PARK9 missense (p.G877R) and a novel heterozygous PARK15 mutation (p.R481C). The PARK9 mutation replaces a crucial residue for the ATPase activity, and is therefore most likely a loss-of-function mutation and disease-causing in homozygous state. The pathogenic significance of the PARK15 single heterozygous mutation remains unclear. In both sibs, DaTSCAN single photon emission computed tomography showed marked nigrostriatal dopaminergic defects, and transcranial magnetic stimulation detected prolonged central motor conduction time. MRI, including T2*-weighted imaging, detected no evidence of brain iron accumulation. This family, the third reported with homozygous PARK9 mutations and the first with mutations in two genes for atypical juvenile parkinsonism, illustrates that PARK9-linked disease might display wide intra-familial clinical variability and milder phenotypes, suggesting the existence of strong, still unknown, modifiers.
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影响因子：
9.9
作者：
Di Fonzo, A.;Chien, H. F.;Bonifati, V.
通讯作者：
Bonifati, V.
DOI：
10.1056/nejmoa0901281
发表时间：
2009-10-22
期刊：
The New England journal of medicine
影响因子：
--
作者：
Sidransky E;Nalls MA;Aasly JO;Aharon-Peretz J;Annesi G;Barbosa ER;Bar-Shira A;Berg D;Bras J;Brice A;Chen CM;Clark LN;Condroyer C;De Marco EV;Dürr A;Eblan MJ;Fahn S;Farrer MJ;Fung HC;Gan-Or Z;Gasser T;Gershoni-Baruch R;Giladi N;Griffith A;Gurevich T;Januario C;Kropp P;Lang AE;Lee-Chen GJ;Lesage S;Marder K;Mata IF;Mirelman A;Mitsui J;Mizuta I;Nicoletti G;Oliveira C;Ottman R;Orr-Urtreger A;Pereira LV;Quattrone A;Rogaeva E;Rolfs A;Rosenbaum H;Rozenberg R;Samii A;Samaddar T;Schulte C;Sharma M;Singleton A;Spitz M;Tan EK;Tayebi N;Toda T;Troiano AR;Tsuji S;Wittstock M;Wolfsberg TG;Wu YR;Zabetian CP;Zhao Y;Ziegler SG
通讯作者：
Ziegler SG
影响因子：
8.6
作者：
Djarmati, Ana;Hagenah, Johann;Klein, Christine
通讯作者：
Klein, Christine
DOI：
10.1016/j.bbrc.2006.02.061
发表时间：
2006-04-21
影响因子：
3.1
作者：
Chang, YF;Cheng, CM;Yuo, CY
通讯作者：
Yuo, CY
影响因子：
4.8
作者：
Hsu, JM;Lee, YCG;Huang, CYF
通讯作者：
Huang, CYF