A novel homozygous Ala529Val LMNA mutation in Turkish patients with mandibuloacral dysplasia
A novel homozygous Ala529Val LMNA mutation in Turkish patients with mandibuloacral dysplasia
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DOI：
10.1210/jc.2004-2560
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发表时间：
2005-09-01
影响因子：
5.8
通讯作者：
Agarwal, AK
中科院分区：
文献类型：
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作者：
Garg, A;Cogulu, O;Agarwal, AK
背景：下颌骨肩关节发育不良(MAD)是一种罕见的常染色体隐性遗传病，其特征是下颌骨和锁骨发育不良、顶骨溶解、颅缝延迟闭合、关节收缩、脂肪营养不良和斑驳的皮肤色素沉着。A型脂肪营养不良伴四肢sc脂肪丢失、颈部和躯干正常或轻度过剩的MAD患者此前已被报道携带LMNA(Lamin A/C)基因的纯合子Arg527His突变。在B型脂肪营养不良伴全身sc脂肪丢失的患者中，我们最近报道了一例携带内切酶锌金属蛋白酶(ZMPSTE24)复合杂合突变的患者，目的：我们的目标是在更多的MAD和A型脂肪营养不良患者中进行LMNA的突变分析。设计和背景：我们在转诊中心研究描述性病例报告。患者：研究对象是来自土耳其的两个家系的一男一女MAD患者。主要观察指标：我们评估了基因型-表型关系。结果：我们现在报道这两个患者都有一种新的纯合子错义突变(约1586C->；T；c指的是LMNA中的cDNA参考序列)，其将位于第529位的保守残基丙氨酸替换为valine。基因内单核苷酸多态分析显示，在两个受影响的受试者的父母中，围绕突变核苷酸的一个共同的单倍型跨越2.5kb，表明突变来自祖先。这名女性患者在月经正常的情况下没有乳房发育，这是一种不同于MAD和Arg527 His LMNA突变的表型。结论：我们认为涉及精氨酸527和丙氨酸529残基的两个纯合子错义LMNA突变导致MAD，但表型略有变化。
Context: Mandibuloacral dysplasia ( MAD) is a phenotypically heterogeneous, rare autosomal recessive disorder characterized by mandibular and clavicular hypoplasia, acroosteolysis, delayed closure of cranial sutures, joint contractures, lipodystrophy, and mottled cutaneous pigmentation. MAD patients with type A lipodystrophy with loss of sc fat from the extremities and normal or slight excess in the neck and truncal regions have been previously reported to carry a homozygous Arg527His mutation in LMNA (Lamin A/C) gene. Among those with type B pattern of lipodystrophy with generalized loss of sc fat, we recently reported a patient carrying compound heterozygous mutations in an endoprotease, zinc metalloproteinase (ZMPSTE24), gene that is involved in posttranslational processing of prelamin A to mature lamin A.Objective: Our objective was to carry out mutational analysis of LMNA in additional patients with MAD and type A lipodystrophy.Design and Setting: We studied descriptive case reports at a referral center.Patients: Subjects were a male and a female patient with MAD who belonged to two pedigrees from Turkey.Main Outcome Measures: We assessed genotype-phenotype relationships.Results: We now report that both these patients have a novel homozygous missense mutation (c. 1586C -> T; c refers to cDNA reference sequence) in LMNA that replaces a well-conserved residue alanine at position 529 to valine. Intragenic single-nucleotide polymorphisms revealed a common haplotype spanning 2.5 kb around the mutated nucleotide in the parents of both the affected subjects, suggesting ancestral origin of the mutation. The female patient had no breast development despite normal menstruation, a phenotype different from that seen in women with MAD and Arg527His LMNA mutation.Conclusions: We conclude that two homozygous missense LMNA mutations involving the arginine 527 and alanine 529 residues cause MAD with subtle variations in phenotype.