Nonsense mutations in folliculin presenting as isolated familial spontaneous pneumothorax in adults
Nonsense mutations in folliculin presenting as isolated familial spontaneous pneumothorax in adults
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DOI：
10.1164/rccm.200501-143oc
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发表时间：
2005-07-01
影响因子：
24.7
通讯作者：
Garcia, CK
中科院分区：
文献类型：
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作者：
Graham, RB;Nolasco, M;Garcia, CK
大约10%的自发性气胸患者有阳性家族史。目的：我们试图确定与气胸易感性相关的DNA序列变异。方法：我们收集了12个家庭，这些家庭至少有两个一级亲属患有自发性气胸。所有受影响的家庭成员都没有明显的与气胸相关的已知遗传疾病的污点。我们使用单倍型分析、DNA测序和突变的限制性片段分析来评估这些家系中的个体。主要结果：在12个家系中，有2个家系的疾病与候选基因座Flcn两侧的标记发生共分离。对关联的等位基因进行测序发现，12个家系中有2个预测会导致过早终止密码子的突变。大多数FLCN基因突变导致一种罕见的疾病，Birt-Hogg-Dube综合征，其特征是常染色体显性遗传多发性良性皮肤病变、肾脏肿瘤、肺小泡和气胸。携带无义突变的家庭成员都没有Birt-Hogg-Dube综合征或肾癌的皮肤表现。对三名受影响的非吸烟者的肺组织进行了病理检查，发现有气泡和潜在的肺气肿。结论：孤立性家族性自发性气胸可由FLCN基因突变引起。由于气胸和/或肺小泡的发展可能是FLCN突变的最早或唯一的临床表现，肺科医生应该警惕该基因在这种家族性肺气肿中的作用。
Approximately 10% of patients who have a spontaneous pneumothorax have a positive family history. Objectives: We sought to identify DNA sequence variations that confer susceptibility to pneumothoraces. Methods: We collected 12 families that had at least 2 first-degree relatives with a spontaneous pneumothorax. All affected family members had no obvious stigmata of known genetic disorders associated with pneumothoraces. We used haplotype analysis, DNA sequencing, and restriction fragment analysis of mutations to evaluate the individuals in these families. Main Results: In 2 of the 12 families the disorder cosegregated with markers flanking a candidate locus, FLCN. Sequencing the linked alleles revealed 2 mutations predicted to introduce premature stop codons in 2 of the 12 families. Most mutations in FLCN cause a rare disease, Birt-Hogg-Dube syndrome, characterized by autosomal dominant inheritance of multiple benign skin lesions, renal tumors, pulmonary blebs, and pneumothoraces. None of the family members with the nonsense mutations had the skin manifestations of Birt-Hogg-Dube syndrome or renal cancer. Pathologic examination of lung tissue from three affected nonsmokers revealed blebs and underlying emphysema. Conclusions: Isolated familial spontaneous pneumothorax can be caused by mutations of the FLCN gene. Because development of a pneumothorax and/or pulmonary blebs may be the earliest or the only clinical manifestation of FLCN mutations, pulmonologists should be alert to the contribution of this gene toward this familial form of emphysema.