Autism spectrum disorder associated with low serotonin in CSF and mutations in the SLC29A4 plasma membrane monoamine transporter (PMAT) gene.
Autism spectrum disorder associated with low serotonin in CSF and mutations in the SLC29A4 plasma membrane monoamine transporter (PMAT) gene.
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DOI：
10.1186/2040-2392-5-43
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发表时间：
2014
期刊：
影响因子：
6.2
通讯作者：
Thöny B
中科院分区：
文献类型：
--
作者：
Adamsen D;Ramaekers V;Ho HT;Britschgi C;Rüfenacht V;Meili D;Bobrowski E;Philippe P;Nava C;Van Maldergem L;Bruggmann R;Walitza S;Wang J;Grünblatt E;Thöny B
自闭症谱系障碍（ASD）患者可能具有低脑5-羟色胺浓度，如脑脊液（CSF）中5-羟色胺终末代谢物5-羟基吲哚乙酸（5 HIAA）所反映的。我们对候选基因SLC 6A 4（SERT）、SLC 29 A4（PMAT）和GCHFR（GFRP）进行测序，然后进行全外显子组分析。已知的SLC 6A 4基因中的杂合p.Gly56Ala突变在ASD和对照人群中同样存在。使用遗传候选基因方法，我们在248例ASD患者中的8例患者中发现，SLC 29 A4质膜单胺转运蛋白（PMAT）基因内的3个新杂合非同义突变中，c.86A > G（p.Asp29Gly）2例，c.412G > A（p.Ala138Thr）5例，c.978T> G（p.Asp326Glu）1例。未受影响的父母的基因组分析证实，这些PMAT突变不是新生的，而是遗传突变。在分析超过15，000条正常对照染色体时，仅在23个等位基因（0.14%）中发现了SLC 29 A4 c.86A > G，而在所有分析的染色体中均未观察到c.412G > A（<0.007%）或c.978 T > G（<0.007%），强调了这三种改变的罕见性。突变PMAT-p. Ala 138 Thr和p.Asp326Glu在细胞中的表达显示对多种底物的转运摄取活性显著降低，包括5-羟色胺、多巴胺和1-甲基-4-苯基吡啶（MPP+），而突变p.Asp29Gly仅对MPP+具有降低的转运活性。至少有两名ASD患者的PMAT-Ala 138 Thr或PMAT-Asp 326 Glu突变改变5-羟色胺转运活性，除了在CSF中低5 HIAA，血液和血小板中的5-羟色胺水平升高。此外，全外显子组测序显示，这两名ASD患者与其未受影响的家庭成员相比，主要在降钙素稳态基因中发生了额外的改变。我们的研究结果将SLC 29 A4突变与ASD人群联系起来，尽管并非总是与低脑血清素有关。PMAT功能障碍被推测为在产前升高5-羟色胺，通过5-羟色胺受体对5-羟色胺网络的发育和局部5-羟色胺合成施加负反馈抑制。两个家族中5-羟色胺稳态基因的外显子组测序说明了ASD中异常5-羟色胺信号传导的更多见解。
Patients with autism spectrum disorder (ASD) may have low brain serotonin concentrations as reflected by the serotonin end-metabolite 5-hydroxyindolacetic acid (5HIAA) in cerebrospinal fluid (CSF). We sequenced the candidate genes SLC6A4 (SERT), SLC29A4 (PMAT), and GCHFR (GFRP), followed by whole exome analysis. The known heterozygous p.Gly56Ala mutation in the SLC6A4 gene was equally found in the ASD and control populations. Using a genetic candidate gene approach, we identified, in 8 patients of a cohort of 248 with ASD, a high prevalence (3.2%) of three novel heterozygous non-synonymous mutations within the SLC29A4 plasma membrane monoamine transporter (PMAT) gene, c.86A > G (p.Asp29Gly) in two patients, c.412G > A (p.Ala138Thr) in five patients, and c.978 T > G (p.Asp326Glu) in one patient. Genome analysis of unaffected parents confirmed that these PMAT mutations were not de novo but inherited mutations. Upon analyzing over 15,000 normal control chromosomes, only SLC29A4 c.86A > G was found in 23 alleles (0.14%), while neither c.412G > A (<0.007%) nor c.978 T > G (<0.007%) were observed in all chromosomes analyzed, emphasizing the rareness of the three alterations. Expression of mutations PMAT-p.Ala138Thr and p.Asp326Glu in cellulae revealed significant reduced transport uptake activity towards a variety of substrates including serotonin, dopamine, and 1-methyl-4-phenylpyridinium (MPP+), while mutation p.Asp29Gly had reduced transport activity only towards MPP+. At least two ASD subjects with either the PMAT-Ala138Thr or the PMAT-Asp326Glu mutation with altered serotonin transport activity had, besides low 5HIAA in CSF, elevated serotonin levels in blood and platelets. Moreover, whole exome sequencing revealed additional alterations in these two ASD patients in mainly serotonin-homeostasis genes compared to their non-affected family members. Our findings link mutations in SLC29A4 to the ASD population although not invariably to low brain serotonin. PMAT dysfunction is speculated to raise serotonin prenatally, exerting a negative feedback inhibition through serotonin receptors on development of serotonin networks and local serotonin synthesis. Exome sequencing of serotonin homeostasis genes in two families illustrated more insight in aberrant serotonin signaling in ASD.
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影响因子：
168.9
作者：
Levy, Susan E.;Mandell, David S.;Schultz, Robert T.
通讯作者：
Schultz, Robert T.
影响因子：
2.7
作者：
Boylan, Carolyn B.;Blue, Mary E.;Hohmann, Christine F.
通讯作者：
Hohmann, Christine F.
影响因子：
4.8
作者：
Engel, K;Zhou, MY;Wang, J
通讯作者：
Wang, J
影响因子：
3.7
作者：
Kane MJ;Angoa-Peréz M;Briggs DI;Sykes CE;Francescutti DM;Rosenberg DR;Kuhn DM
通讯作者：
Kuhn DM
影响因子：
3.3
作者：
Dahlin, A.;Xia, L.;Wang, J.
通讯作者：
Wang, J.