Germline and mosaic mutations of FLN1 in men with periventricular heterotopia
Germline and mosaic mutations of FLN1 in men with periventricular heterotopia
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DOI：
10.1212/01.wnl.0000132818.84827.4d
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发表时间：
2004-07-13
期刊：
影响因子：
9.9
通讯作者：
Parrini, E
中科院分区：
文献类型：
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作者：
Guerrini, R;Mei, D;Parrini, E
目的：描述4例由FLN 1基因突变引起的室周结节性异位症（PNH）的表型谱和遗传学特征。背景资料：由FLN 1突变（MIM #300049）引起的X连锁PNH意味着男孩的产前或产后早期死亡率和受影响妇女的女儿的50%复发风险。研究方法：对9名受影响的个体（包括3名男性）进行了临床检查、认知测试、MRI和血淋巴细胞和单根发根突变分析（变性高效液相色谱和直接测序）。对一名受影响的男孩进行了脑神经病理学研究。结果如下：在两个家庭中，错义突变从母亲传给儿子（Met 102 Val）和从父亲传给女儿（Ser 149 Phe），导致两种性别的轻度表型，包括单侧PNH。在第三个家族中，一名男子在白细胞DNA和发根上的A > G取代（内含子11受体剪接位点）（突变= 42%和69%）。单毛根分析证实，突变不存在于所有的外胚层衍生细胞。一个健康的女儿从她父亲的野生型生殖细胞群体中遗传了X染色体。在第四个家族中，8个碱基缺失（AGGAG-GTG，内含子25供体剪接位点）导致男孩过早死亡。一名新生儿男孩的尸检研究显示PNH和心血管、泌尿生殖系统和肠道畸形。结论：男性FLN 1突变引起的室周结节性异位具有广泛的临床谱，并且由不同的遗传机制引起，包括体细胞嵌合体。FLN 1突变分析应支持室周结节性异位男性的遗传咨询。
Objective: To describe the phenotypic spectrum and genetics of periventricular nodular heterotopia (PNH) caused by FLN1 mutations in four men. Background: X-linked PNH caused by FLN1 mutations (MIM #300049) implies prenatal or early postnatal lethality in boys and 50% recurrence risk in daughters of affected women. Methods: Clinical examination, cognitive testing, MRI, and mutation analysis (denaturing high-performance liquid chromatography and direct sequencing) on blood lymphocytes and single hair roots were performed for nine affected individuals, including three men. Neuropathologic study of the brain was performed for an affected boy. Results: In two families, missense mutations were transmitted from mother to son (Met102Val) and from father to daughter (Ser149Phe), causing mild phenotypes in both genders, including unilateral PNH. In a third family, a man was mosaic for an A > G substitution (intron 11 acceptor splice site) on leukocyte DNA and hair roots (mutant = 42% and 69%). Single hair root analysis confirmed that the mutation was not present in all ectodermal derivative cells. A healthy daughter had inherited the X chromosome from her father's wild-type germinal cell population. In the fourth family, an eight-base deletion (AGGAG-GTG, intron 25 donor splice site) led to early deaths of boys. Postmortem study in a newborn boy revealed PNH and cardiovascular, genitourinary, and gut malformations. Conclusions: Periventricular nodular heterotopia caused by FLN1 mutations in men has a wide clinical spectrum and is caused by different genetic mechanisms, including somatic mosaicism. Mutation analysis of FLN1 should support genetic counseling in men with periventricular nodular heterotopia.