Helicase-inactivating BRIP1 mutation yields Fanconi anemia with microcephaly and other congenital abnormalities.
Helicase-inactivating BRIP1 mutation yields Fanconi anemia with microcephaly and other congenital abnormalities.
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DOI：
10.1101/mcs.a005652
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发表时间：
2020-10
影响因子：
1.8
通讯作者：
Kanaan MN
中科院分区：
文献类型：
--
作者：
Kamal L;Pierce SB;Canavati C;Rayyan AA;Jaraysa T;Lobel O;Lolas S;Norquist BM;Rabie G;Zahdeh F;Levy-Lahad E;King MC;Kanaan MN
范可尼贫血是一种遗传和表型异质性疾病，其特征为先天异常、骨髓衰竭、癌症和染色体对 DNA 交联剂的敏感性。导致范可尼贫血的 22 个基因之一是 BRIP1，其中双等位基因截短突变导致范可尼贫血 J 组，而单等位基因截短突变则易患某些癌症。然而，在已报道的 1000 多个 BRIP1 错义突变中，很少有功能得到表征。我们评估了 BRIP1 p.R848H (c.2543G > A) 的功能结果，该基因在两个患有低出生体重、小头畸形、上肢畸形和肛门闭锁的表亲中是纯合的，对患者细胞的染色体断裂分析显示丝裂霉素 C 敏感性增加。 BRIP1 p.R848H 改变催化 DNA 解旋酶结构域中高度保守的残基。我们发现 BRIP1 p.R848H 会导致解旋酶活性缺陷。已在多个癌症患者中报告了这种错义的杂合性，但在缺乏功能研究的情况下，被归类为意义未知。我们的结果支持这种突变对于纯合子中的范可尼贫血以及杂合子携带者中的癌症易感性增加具有致病性。
Fanconi anemia is a genetically and phenotypically heterogeneous disorder characterized by congenital anomalies, bone marrow failure, cancer, and sensitivity of chromosomes to DNA cross-linking agents. One of the 22 genes responsible for Fanconi anemia is BRIP1, in which biallelic truncating mutations lead to Fanconi anemia group J and monoallelic truncating mutations predispose to certain cancers. However, of the more than 1000 reported missense mutations in BRIP1, very few have been functionally characterized. We evaluated the functional consequence of BRIP1 p.R848H (c.2543G > A), which was homozygous in two cousins with low birth weight, microcephaly, upper limb abnormalities, and imperforate anus and for whom chromosome breakage analysis of patient cells revealed increased mitomycin C sensitivity. BRIP1 p.R848H alters a highly conserved residue in the catalytic DNA helicase domain. We show that BRIP1 p.R848H leads to a defect in helicase activity. Heterozygosity at this missense has been reported in multiple cancer patients but, in the absence of functional studies, classified as of unknown significance. Our results support that this mutation is pathogenic for Fanconi anemia in homozygotes and for increased cancer susceptibility in heterozygous carriers.
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影响因子：
14.9
作者：
Bharti SK;Sommers JA;Awate S;Bellani MA;Khan I;Bradley L;King GA;Seol Y;Vidhyasagar V;Wu Y;Abe T;Kobayashi K;Shin-Ya K;Kitao H;Wold MS;Branzei D;Neuman KC;Brosh RM Jr
通讯作者：
Brosh RM Jr
影响因子：
48
作者：
Gibson, Daniel G.;Young, Lei;Smith, Hamilton O.
通讯作者：
Smith, Hamilton O.
影响因子：
4.8
作者：
Guo, Manhong;Vidhyasagar, Venkatasubramanian;Wu, Yuliang
通讯作者：
Wu, Yuliang
影响因子：
30.8
作者：
Levitus, M;Waisfisz, Q;Joenje, H
通讯作者：
Joenje, H
影响因子：
4
作者：
Easton DF;Lesueur F;Decker B;Michailidou K;Li J;Allen J;Luccarini C;Pooley KA;Shah M;Bolla MK;Wang Q;Dennis J;Ahmad J;Thompson ER;Damiola F;Pertesi M;Voegele C;Mebirouk N;Robinot N;Durand G;Forey N;Luben RN;Ahmed S;Aittomäki K;Anton-Culver H;Arndt V;Australian Ovarian Cancer Study Group;Baynes C;Beckman MW;Benitez J;Van Den Berg D;Blot WJ;Bogdanova NV;Bojesen SE;Brenner H;Chang-Claude J;Chia KS;Choi JY;Conroy DM;Cox A;Cross SS;Czene K;Darabi H;Devilee P;Eriksson M;Fasching PA;Figueroa J;Flyger H;Fostira F;García-Closas M;Giles GG;Glendon G;González-Neira A;Guénel P;Haiman CA;Hall P;Hart SN;Hartman M;Hooning MJ;Hsiung CN;Ito H;Jakubowska A;James PA;John EM;Johnson N;Jones M;Kabisch M;Kang D;kConFab Investigators;Kosma VM;Kristensen V;Lambrechts D;Li N;Lifepool Investigators;Lindblom A;Long J;Lophatananon A;Lubinski J;Mannermaa A;Manoukian S;Margolin S;Matsuo K;Meindl A;Mitchell G;Muir K;NBCS Investigators;Nevelsteen I;van den Ouweland A;Peterlongo P;Phuah SY;Pylkäs K;Rowley SM;Sangrajrang S;Schmutzler RK;Shen CY;Shu XO;Southey MC;Surowy H;Swerdlow A;Teo SH;Tollenaar RA;Tomlinson I;Torres D;Truong T;Vachon C;Verhoef S;Wong-Brown M;Zheng W;Zheng Y;Nevanlinna H;Scott RJ;Andrulis IL;Wu AH;Hopper JL;Couch FJ;Winqvist R;Burwinkel B;Sawyer EJ;Schmidt MK;Rudolph A;Dörk T;Brauch H;Hamann U;Neuhausen SL;Milne RL;Fletcher O;Pharoah PD;Campbell IG;Dunning AM;Le Calvez-Kelm F;Goldgar DE;Tavtigian SV;Chenevix-Trench G
通讯作者：
Chenevix-Trench G