Phenotypic and genetic heterogeneity in congenital generalized lipodystrophy
Phenotypic and genetic heterogeneity in congenital generalized lipodystrophy
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DOI：
10.1210/jc.2003-030855
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发表时间：
2003-10-01
影响因子：
5.8
通讯作者：
Garg, A
中科院分区：
文献类型：
--
作者：
Agarwal, AK;Simha, V;Garg, A
先天性全身性脂肪营养不良（CGL）是一种罕见的常染色体隐性遗传病，其特征是出生时几乎完全没有脂肪组织。最近，在染色体9q34和11q13的家系中分别报道了1-酰基甘油-3-磷酸o -酰基转移酶2 （AGPAT2）和Berardinelli-Seip先天性脂肪营养不良2 （BSCL2）基因突变。关于不同亚型CGL之间表型差异的数据有限。此外，是否存在CGL的其他基因座仍然未知。因此，我们针对AGPAT2和BSCL2基因座对45个CGL家系进行了基因分型，并比较了不同亚型的表型。26个家系在AGPAT2基因中存在突变，包括7个新变体，11个家系在BSCL2基因中存在突变，包括5个新变体。8个家系的两个基因都没有实质性的改变。其中，三个信息丰富的家系显示与跨越AGPAT2和BSCL2位点的标记没有关联，并且在6个受影响的受试者中，AGPAT2和BSCL2的转录本是正常的。所有CGL亚型均显示糖尿病、高甘油三酯血症和黑棘皮病的高发率。然而，与其他亚型相比，BSCL2突变患者的血清瘦素水平较低，糖尿病发病较早，轻度智力迟钝的患病率较高。我们得出结论，除了AGPAT2和BSCL2，可能还有其他基因座与CGL有关。CGL患者的遗传异质性伴随着表型异质性。
Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by near complete absence of adipose tissue from birth. Recently, mutations in 1-acylglycerol-3-phosphate O-acyltransferase 2 (AGPAT2) and Berardinelli-Seip congenital lipodystrophy 2 (BSCL2) genes were reported in pedigrees linked to chromosomes 9q34 and 11q13, respectively. There are limited data regarding phenotypic differences between the various subtypes of CGL. Furthermore, whether there are additional loci for CGL remains unknown. Therefore, we genotyped 45 pedigrees with CGL for AGPAT2 and BSCL2 loci and compared the phenotypes in the various subtypes. Twenty-six pedigrees harbored mutations, including seven novel variants, in the AGPAT2 gene, and 11 pedigrees harbored mutations in the BSCL2 gene, including five novel variants. Eight pedigrees had no substantial alterations in either gene. Of these, three informative pedigrees showed no linkage to markers spanning the AGPAT2 and BSCL2 loci, and in six of the affected subjects, the transcripts of AGPAT2 and BSCL2 were normal. All subtypes of CGL showed high prevalence of diabetes, hypertriglyceridemia, and acanthosis nigricans. However, patients with BSCL2 mutations had lower serum leptin levels, an earlier onset of diabetes, and higher prevalence of mild mental retardation compared with other subtypes. We conclude that besides AGPAT2 and BSCL2, there may be additional loci for CGL. The genetic heterogeneity in CGL patients is accompanied by phenotypic heterogeneity.