Human PTCHD3 nulls: rare copy number and sequence variants suggest a non-essential gene.
Human PTCHD3 nulls: rare copy number and sequence variants suggest a non-essential gene.
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DOI：
10.1186/1471-2350-12-45
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发表时间：
2011-03-26
影响因子：
--
通讯作者：
Scherer SW
中科院分区：
文献类型：
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作者：
Ghahramani Seno MM;Kwan BY;Lee-Ng KK;Moessner R;Lionel AC;Marshall CR;Scherer SW
拷贝数变异（CNVs）可以导致不同程度的适应度和/或疾病易感性。最近的研究表明，与人类参考序列组合相比，任何给定基因组中至少有1%的拷贝数是可变的。在正常人群中发现的纯合缺失（或CNV null）特别令人感兴趣，因为它们可能用于定义人类生物学中的非必需基因。在研究自闭症谱系障碍（ASDs） CNV的基因组筛选中，我们在染色体10p12.1上发现了一个杂合缺失，该缺失跨越了包含3 （PTCHD3）基因的patch -domain，频率约为1.4%（6/427）。这一发现似乎很有趣，因为最近发现了另一个包含补丁结构域的基因（PTCHD1）在ASD中的作用。对另外177个ASD先证进行筛查，发现另外两个杂合缺失，使频率达到1.3%（8/604）。在北美和北欧联合对照人群中，缺失频率约为0.73%(27/3,695)，以欧洲血统为主。覆盖全球人群的人类基因组多样性面板（HGDP-CEPH）筛选结果显示，7/ 1043名无亲缘关系个体中存在缺失，而检测到的缺失仅限于欧洲/地中海/中东血统的个体。断点映射在所有病例和对照组中产生相同的102,624 bp缺失，表明共同的祖先事件。有趣的是，这种CNV发生在人类和小鼠之间的synsyny断裂中。然而，考虑到所有数据，没有观察到这些罕见的PTCHD3缺失与ASD的显著关联。尽管如此，我们的RNA表达研究在几种组织中检测到PTCHD3，并且表征了PTCHD3的一种新的较短的异构体。在转染的COS-7细胞中，PTCHD3异构体在内质网中与钙连连蛋白共定位。Ptc结构域的存在表明PTCHD3在通过Hedgehog （Hh）信号通路介导的各种生物过程中发挥作用。然而，进一步的研究发现，一个个体携带纯合缺失（PTCHD3缺失），没有ASD或任何其他明显的异常表型。其他缺失个体的PTCHD3外显子测序显示复合点突变也导致null状态。我们的数据表明，PTCHD3在一些人类中可能是一个非必需基因，在10p12.1位点鉴定这种新型CNV将有助于群体和疾病研究。
Copy number variations (CNVs) can contribute to variable degrees of fitness and/or disease predisposition. Recent studies show that at least 1% of any given genome is copy number variable when compared to the human reference sequence assembly. Homozygous deletions (or CNV nulls) that are found in the normal population are of particular interest because they may serve to define non-essential genes in human biology. In a genomic screen investigating CNV in Autism Spectrum Disorders (ASDs) we detected a heterozygous deletion on chromosome 10p12.1, spanning the Patched-domain containing 3 (PTCHD3) gene, at a frequency of ~1.4% (6/427). This finding seemed interesting, given recent discoveries on the role of another Patched-domain containing gene (PTCHD1) in ASD. Screening of another 177 ASD probands yielded two additional heterozygous deletions bringing the frequency to 1.3% (8/604). The deletion was found at a frequency of ~0.73% (27/3,695) in combined control population from North America and Northern Europe predominately of European ancestry. Screening of the human genome diversity panel (HGDP-CEPH) covering worldwide populations yielded deletions in 7/1,043 unrelated individuals and those detected were confined to individuals of European/Mediterranean/Middle Eastern ancestry. Breakpoint mapping yielded an identical 102,624 bp deletion in all cases and controls tested, suggesting a common ancestral event. Interestingly, this CNV occurs at a break of synteny between humans and mouse. Considering all data, however, no significant association of these rare PTCHD3 deletions with ASD was observed. Notwithstanding, our RNA expression studies detected PTCHD3 in several tissues, and a novel shorter isoform for PTCHD3 was characterized. Expression in transfected COS-7 cells showed PTCHD3 isoforms colocalize with calnexin in the endoplasmic reticulum. The presence of a patched (Ptc) domain suggested a role for PTCHD3 in various biological processes mediated through the Hedgehog (Hh) signaling pathway. However, further investigation yielded one individual harboring a homozygous deletion (PTCHD3 null) without ASD or any other overt abnormal phenotype. Exon sequencing of PTCHD3 in other individuals with deletions revealed compound point mutations also resulting in a null state. Our data suggests that PTCHD3 may be a non-essential gene in some humans and characterization of this novel CNV at 10p12.1 will facilitate population and disease studies.
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