Fine structure mapping of CIAS1:: identification of an ancestral haplotype and a common FCAS mutation, L353P
Fine structure mapping of CIAS1:: identification of an ancestral haplotype and a common FCAS mutation, L353P
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DOI：
10.1007/s00439-002-0860-x
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发表时间：
2003-02-01
期刊：
影响因子：
5.3
通讯作者：
Kolodner, RD
中科院分区：
文献类型：
--
作者：
Hoffman, HM;Gregory, SG;Kolodner, RD
家族性寒冷自身炎症综合征（FCAS）是一种外显率较高的常染色体显性炎症性疾病，其特征是全身接触寒冷后出现皮疹、关节痛、发热、结膜炎和白细胞增多。 FCAS 先前被定位到染色体 1q44 上的 10 cM 区域，随后确定了负责 FCAS 的基因 (CIAS1)。在本文中，我们描述了 FCAS 基因座的物理和遗传图谱，并报告了一个大的祖先单倍型和一个新的致病突变。开发了约 3 Mb 的 BAC 重叠群，随后用于高通量测序。我们利用北美四个大型 FCAS 系列中的罕见交叉事件确定了 4 cM 的关键区域。在四个家族中的三个中发现了异常大的共享单倍型（40 cM）。我们在所有四个家族的 CIAS1 外显子 3 中发现了一个杂合错义突变 (T1058C=L353P)，该突变是文献中描述的绝大多数 FCAS 病例的原因。我们还报告了基因内单核苷酸多态性的综合列表。此处提供的数据将帮助其他人研究 1q44 区域，并帮助临床医生诊断 FCAS。
Familial cold autoinflammatory syndrome (FCAS) is an autosomal dominant inflammatory disease with a high degree of penetrance that is characterized by episodes of rash, arthralgia, fever, conjunctivitis, and leukocytosis after generalized exposure to cold. FCAS was previously mapped to a 10-cM region on chromosome 1q44, and subsequently the gene (CIAS1) responsible for FCAS was identified. In this paper, we describe the physical and genetic mapping of the FCAS locus, and we report a large ancestral haplotype and a new disease-causing mutation. A BAC contig of approximately 3 Mb was developed and subsequently used for high throughput sequencing. We identified a critical region of 4 cM using rare crossover events in four large North American FCAS families. An unusually large shared haplotype (40 cM) was identified in three of the four families. We found a single heterozygous missense mutation (T1058C=L353P) in exon 3 of CIAS1 in all four families that is responsible for the large majority of FCAS cases described in the literature. We also report a comprehensive list of intragenic single nucleotide polymorphisms. The data provided here will assist others researching the 1q44 region and will aid clinicians in the diagnosis of FCAS.