Identification of a locus for maturity-onset diabetes of the young on chromosome 8p23
Identification of a locus for maturity-onset diabetes of the young on chromosome 8p23
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DOI：
10.2337/diabetes.53.5.1375
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发表时间：
2004-05-01
期刊：
影响因子：
7.7
通讯作者：
Doria, A
中科院分区：
文献类型：
--
作者：
Kim, SH;Ma, XW;Doria, A
年轻人成熟型糖尿病（MODY）是一种常染色体显性遗传的年轻发病的糖尿病亚型。迄今为止，已经发现了六个MODY基因。为了确定其他MODY基因座，我们对21个美国大家庭（15个白色和6个少数民族，共237个个体）进行了基因组扫描，其中MODY不是由已知的MODY基因引起的。7个染色体区域（1 q42、2 q24、2 q37、4p 13、8 p23、11 p15和19 q12）在初始筛选中具有大于或等于1.00的参数异质性比值对数（HLOD）或大于或等于0.59的非参数比值对数（LOD）（P小于或等于0.05）。在这些基因座上对额外的标记进行分型以将间距减小到2- 3cM后，在8 p23上检测到显著的连锁（在D8 S1130处HLOD = 3.37，在D8 S265处非参数LOD = 3.66; P = 2 X 10（-5）），其中定位有4.7 Mb倒位多态性。30%的家庭（21个家庭中的6个）与该地区有联系。染色体2 q37上的另一个连锁峰，在D2 S345/D2 S2968处的HLOD为1.96，在另外25%的家族中（21个家族中的5个）解释了糖尿病。所有6个少数民族家庭都在与这些位点连锁的11个家庭中。其他位点的HLOD均未超过1.50。总之，我们已经在8 p23上发现了一个MODY基因座，该基因座导致了很大一部分与已知MODY基因无关的MODY病例中的糖尿病。另一个新的MODY位点可能存在于2 q37。克隆这些新的MODY基因可以为与常见2型糖尿病病因相关的疾病途径提供见解。
Maturity-onset diabetes of the young (MODY) is a subtype of diabetes defined by an autosomal dominant inheritance and a young onset. Six MODY genes have been discovered to date. To identify additional MODY loci, we conducted a genome scan in 21 extended U.S. families (15 white and 6 from minorities, for a total of 237 individuals) in which MODY was not caused by known MODY genes. Seven chromosomal regions (1q42, 2q24, 2q37, 4p13, 8p23, 11p15, and 19q12) had a parametric heterogeneity logarithm of odds (HLOD) greater than or equal to1.00 or a nonparametric logarithm of odds (LOD) greater than or equal to 0.59 (P less than or equal to 0.05) in the initial screen. After typing additional markers at these loci to reduce the spacing to 2-3 cM, significant linkage was detected on 8p23 (HLOD = 3.37 at D8S1130 and nonparametric LOD = 3.66; P = 2 X 10(-5) at D8S265), where a 4.7-Mb inversion polymorphism is located. Thirty percent of the families (6 of 21) were linked with this region. Another linkage peak on chromosome 2q37 with an HLOD of 1.96 at D2S345/ D2S2968 accounted for diabetes in an additional 25% of families (5 of 21). All 6 minority families were among the 11 families linked to these loci. None of the other loci followed up had an HLOD exceeding 1.50. In summary, we have identified a MODY locus on 8p23 that accounts for diabetes in a substantial proportion of MODY cases unlinked to known MODY genes. Another novel MODY locus may be present on 2q37. Cloning these new MODY genes may offer insights to disease pathways that are relevant to the cause of common type 2 diabetes.