Identification of a Hypomorphic FANCG Variant in Bernese Mountain Dogs.
Identification of a Hypomorphic FANCG Variant in Bernese Mountain Dogs.
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作者：
伯尔尼山犬（BMDs）的总体癌症发病率为50%，其中一半是由一种罕见的肿瘤组织细胞肉瘤（HS）组成。虽然最近的研究已经确定了MAPK通路中的驱动突变，但关键易感基因的鉴定一直难以捉摸。研究已经确定了几个与BMD中HS易感性相关的基因座，包括MTAP/CDKN 2A区域附近，但尚未确定致病性编码变体。在这里，我们报告的编码FANCG的基因，MTAP/CDKN 2A基因座附近的编码多态性的存在。该变体位于蛋白质的保守区域，似乎对BMD具有特异性。犬成纤维细胞来源于狗纯合子为这种变异是顺铂过敏。我们发现这种犬FANCG变异体和先前定义的人类亚型FANCG等位基因在DNA修复中具有相似的缺陷。然而，我们的数据也表明，这种变异既不是必要的，也不足以发展HS。此外，该FANCG等位基因纯合的BMD不显示与范可尼贫血（FA）相关的特征性表型，如贫血、身材矮小、不育或较早的HS发病年龄。这与FA缺陷小鼠中的发现相似，这些小鼠在没有加剧FA缺陷的继发性基因突变的情况下不会发生明显的FA。总之，我们的数据表明，在FA通路中存在缺陷的狗与小鼠一样，天生对FA的发展具有抵抗力。
Bernese mountain dogs (BMDs), have an overall cancer incidence of 50%, half of which is comprised of an otherwise rare tumor, histiocytic sarcoma (HS). While recent studies have identified driver mutations in the MAPK pathway, identification of key predisposing genes has been elusive. Studies have identified several loci to be associated with predisposition to HS in BMDs, including near the MTAP/CDKN2A region, but no causative coding variant has been identified. Here we report the presence of a coding polymorphism in the gene encoding FANCG, near the MTAP/CDKN2A locus. This variant is in a conserved region of the protein and appears to be specific to BMDs. Canine fibroblasts derived from dogs homozygous for this variant are hypersensitive to cisplatin. We show this canine FANCG variant and a previously defined hypomorphic FANCG allele in humans impart similar defects in DNA repair. However, our data also indicate that this variant is neither necessary nor sufficient for the development of HS. Furthermore, BMDs homozygous for this FANCG allele display none of the characteristic phenotypes associated with Fanconi anemia (FA) such as anemia, short stature, infertility, or an earlier age of onset for HS. This is similar to findings in FA deficient mice, which do not develop overt FA without secondary genetic mutations that exacerbate the FA deficit. In sum, our data suggest that dogs with deficits in the FA pathway are, like mice, innately resistant to the development of FA.
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影响因子：
28.2
作者：
Diamond EL;Durham BH;Haroche J;Yao Z;Ma J;Parikh SA;Wang Z;Choi J;Kim E;Cohen-Aubart F;Lee SC;Gao Y;Micol JB;Campbell P;Walsh MP;Sylvester B;Dolgalev I;Aminova O;Heguy A;Zappile P;Nakitandwe J;Ganzel C;Dalton JD;Ellison DW;Estrada-Veras J;Lacouture M;Gahl WA;Stephens PJ;Miller VA;Ross JS;Ali SM;Briggs SR;Fasan O;Block J;Héritier S;Donadieu J;Solit DB;Hyman DM;Baselga J;Janku F;Taylor BS;Park CY;Amoura Z;Dogan A;Emile JF;Rosen N;Gruber TA;Abdel-Wahab O
通讯作者：
Abdel-Wahab O
影响因子：
4.3
作者：
Bakker ST;de Winter JP;te Riele H
通讯作者：
te Riele H
影响因子：
3.8
作者：
Fyfe, John C.;Hemker, Shelby L.;Giger, Urs
通讯作者：
Giger, Urs
影响因子：
2.4
作者：
Affolter, VK;Moore, PF
通讯作者：
Moore, PF
DOI：
10.1001/jama.2015.13134
发表时间：
2015-11-03
期刊：
JAMA
影响因子：
--
作者：
Abegglen LM;Caulin AF;Chan A;Lee K;Robinson R;Campbell MS;Kiso WK;Schmitt DL;Waddell PJ;Bhaskara S;Jensen ST;Maley CC;Schiffman JD
通讯作者：
Schiffman JD