Roberts Penelope S, Chung Joon, Jozwiak Sergiusz, Dabora Sandra L, Franz David N, Thiele Elizabeth A, Kwiatkowski David J
Hematology Division, Brigham & Women's Hospital, Harvard Medical School, 221 Longwood Ave., Boston, MA 02115, USA.
Hum Genet. 2002 Jul;111(1):96-101. doi: 10.1007/s00439-002-0738-y. Epub 2002 Jun 7.
Inactivating mutations in the TSC2 gene, consisting of 41coding exons in 40 kb on 16p13, cause the hamartoma syndrome tuberous sclerosis. During TSC2 mutational analysis we identified ten SNPs that occur within or close to exon boundaries at minor allele frequencies greater than 5%. We determined the haplotypes for six of these SNPs and the microsatellite marker kg8 in the 3' region of TSC2 in a set of 40 parent-child trios. The most common haplotypes accounted for 53%, 11%, 6%, and 5% of chromosomes. Thirty-eight TSC2 mutation-bearing haplotypes had a similar distribution, indicating that there was no haplotype that predisposed to mutation in this region of TSC2. Family analysis was possible in 12 sporadic cases, and indicated that the mother was the parent of origin in 7 cases (3 point mutations, 2 small deletions, 2 large deletions), while the father was in 5 cases (2 point mutations, 3 small deletions). We conclude that TSC2 mutations occur at substantial frequency on both the maternally and paternally derived TSC2 alleles, in contrast to many other genetic diseases including NF1. The observations have implications for genetic counseling in TSC.
TSC2基因的失活突变可导致错构瘤综合征结节性硬化症，该基因位于16p13上40kb区域，由41个编码外显子组成。在TSC2突变分析过程中，我们鉴定出10个单核苷酸多态性（SNP），这些SNP位于外显子边界内或其附近，次要等位基因频率大于5%。我们在一组40个亲子三联体中确定了其中6个SNP以及TSC2基因3'区域微卫星标记kg8的单倍型。最常见的单倍型分别占染色体的53%、11%、6%和5%。38个携带TSC2突变的单倍型分布相似，这表明在TSC2基因的该区域不存在易发生突变的单倍型。对12例散发病例进行家系分析发现，7例病例的起源亲本为母亲（3个点突变、2个小缺失、2个大缺失），5例病例的起源亲本为父亲（2个点突变、3个小缺失）。我们得出结论，与包括NF1在内的许多其他遗传疾病不同，TSC2突变在母源和父源TSC2等位基因上均有相当高的发生频率。这些观察结果对结节性硬化症的遗传咨询具有重要意义。
