Novel mutations in the SDHD gene in pedigrees with familial carotid body paraganglioma and sensorineural hearing loss
Novel mutations in the SDHD gene in pedigrees with familial carotid body paraganglioma and sensorineural hearing loss
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DOI：
10.1002/gcc.1142
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发表时间：
2001-07-01
影响因子：
3.7
通讯作者：
Schofield, PR
中科院分区：
文献类型：
--
作者：
Badenhop, RF;Cherian, S;Schofield, PR
副神经节瘤（PGL）是一种罕见的疾病，以头颈部肿瘤为特征。10%至50%的PGL病例是家族性的，这种疾病是常染色体显性的，受年龄依赖性外显率和印记的影响。副神经节瘤基因（PGLI）已定位于11q22.3-q23，最近发现了SDHD基因的种系突变。sddd区域包含另一个基因DPP2/TIMM8B，该基因的同源性导致Mohr-Tranebjaerg综合征中出现的肌张力障碍和耳聋。使用四个PGL家系，其中两个显示PGL与感音神经性听力损失或耳鸣共遗传，分析14个微卫星标记为PGLI位点的连锁提供了支持。序列分析鉴定出sddd基因外显子1和外显子3的新突变，包括外显子3上新的两个碱基对缺失，在67号位置产生过早终止密码子；外显子3上新的三个碱基对缺失导致tyr93缺失；外显子3的错义突变导致Leu-81被Pro-81取代；外显子1上新的G-to-C取代导致Met-1取代Ile-1。DPP2/TIMM8B基因未检测到碱基变化。在sddd突变位点没有明显的杂合性损失。然而，肿瘤样本的RT-PCR分析显示突变（父本）等位基因的单等位基因表达与预期的印迹一致。这在之前的研究中还没有发现。SDHD基因的遗传和表达与PGLI基因受基因组印记的影响是一致的。(C) 2001 Wiley-Liss, Inc。
Paraganglioma (PGL) is a rare disorder characterized by tumors of the head and neck region. Between 10% and 50% of cases of PGL are familial, and the disease is autosomal dominant and subject to age-dependent penetrance and imprinting. The paraganglioma gene (PGLI) has been mapped to 11q22.3-q23, and recently germline mutations in the SDHD gene have been identified. The SDHD region contains another gene, DPP2/TIMM8B, the homolog of which causes dystonia and deafness seen in Mohr-Tranebjaerg syndrome. Using four PGL pedigrees, two of which exhibit coinheritance of PGL and sensorineural hearing loss or tinnitus, analysis of 14 microsatellite markers provided support for linkage to the PGLI locus. Sequence analysis identified novel mutations in exon 1 and exon 3 of the SDHD gene, including a novel two base pair deletion in exon 3 creating a premature stop codon at position 67; a novel three base pair deletion in exon 3 resulting in the loss of Tyr-93; a missense mutation in exon 3 resulting in the substitution of Leu-81 for Pro-81; and a novel G-to-C substitution in exon 1 resulting in the substitution of Met-1 for Ile-1. No base changes were detected in the DPP2/TIMM8B gene. There was no apparent loss of heterozygosity at the site of the SDHD mutations. However, RT-PCR analysis of tumor samples showed monoallelic expression of the mutant (paternal) allele as expected for imprinting. This has not previously been shown for this disorder. The inheritance and expression of the SDHD gene is consistent with the PGLI gene being subject to genomic imprinting. (C) 2001 Wiley-Liss, Inc.