Mutation Analysis Of LMNA Gene For Hutchinson-Gilford Progeria Syndrome And Dilated Cardiomyopathy

Chapter1. Mutation analysis of LMNA gene in Chinese Han HGPS patientsHutchinson-Gilford progeria syndrome(HGPS,OMIM176670) is a sporadic, extremely rare, early onset and severe premature aging disorder. Hutchinson-Gilford progeria syndrome is a rare disorder characterized by short stature, low body weight, early loss of hair, lipodystrophy, scleroderma, decreased joint mobility, osteolysis, and facial features that resemble aged persons. The onset of HGPS is within1year old, until2years old it can be diagnosed. The average life expectancy for a patient with HGPS is13years old, with an age range of7to27years old, occationally to45years old, the primary death cause of HGPS is the cardiovascular diseases. The patients of HGPS are almost children. The incidence of classic progeria has been estimated to be1per4-8million live births. The disease affects more males than females (M:F=1.5:1) and is more frequent in Caucasians(97%of all the cases reported). At present, no incidence of progeria is reported in China.Researches show that LMNA gene mutation is relative to HGPS. The different LMNA gene mutation found in different HGPS patients may have similar phenotypes. In addition, the same mutations can cause different patients showing distinct disease phenotypes. There were very few studies on Chinese HGPS patients and LMNA gene mutation screening, and the very big difference in the racial genetic susceptibility factor was observed, therefore, screening LMNA gene mutation on Chinese HGPS patients and their family members may contribute to understand the association between LMNA gene variation and HGPS in the Chinese Han nationality.In order to clarify the genetic basis in Chinese Han HGPS population, this study collected1Chinese Han HGPS pedigree and100normal controls. By PCR and direct sequencing we analyzed the LMNA gene mutation in the HGPS family members and100normal controls.Our results revealed all members in the HGPS pedigree carried LMNA gene mutations c.1579C> T, this variation resulted in a change of arginine to cysteine (R527C). The proband and his brother were LMNA homozygous change c.1579C>T, parents were LMNA heterozygous change c.1579C>T. We have not found the same mutation in the100normal controls.This study indicates that LMNA gene homozygous mutation R527C lead to the affected children suffering from HGPS. Chapter2. Mutation analysis of LMNA gene in Chinese Han DCM patientsDilated cardiomyopathy (DCM, OMIM115200), the most common type of cardiomyopathy, is a group of diseases with genetically highly heterogeneity and clinical diversity, characterized by cardiac dilation and systolic dysfunction leading to congestive heart failure and sudden death. The main clinical manifestations include heart failure, thrombosis embolism, arrhythmia and sudden death. Dilated cardiomyopathy is relatively slow onset. The prevalence in male compared to female is2.5to1, the onset age is in20～50years old, but individual age of onset tends to be younger now.5years of the fatality rate is15%～50%, the survival rate of less than50%. DCM is mostly sporadic, while Europe and America relevant statistics annual incidence of approximately7/100000. In Japan, the incidence of iDCM is relatively low, with prevalence of1.2/100000. In China, in1992, the survey found that the incidence of DCM was1.3/10000in Nanjing. In recent years, at home and abroad the trendency is rising.At present, DCM etiology and pathogenesis is not fully understood. But related studies proved that DCM was associated with genetic factors significantly. About35%of DCM patients are familial.27chromosomal loci for DCM have been described. So far mutations in16genes have been shown to cause autosomal dominant familial dilated cardiomyo- pathy (FDCM). The LMNA gene is causative for FDCM with block of virulence. According to the current literature, LMNA mutations including R60G, L85R, K97E, E111X, E161K, Arg190Trp, N195K, E203G, E317K, R377H, L59R, S573L, Glu53Val, Glu186Lys can cause DCM, these mutations can be seen in all exon12occur.Our previous study has identified a candidate gene for DCM, to further explore the genetic basis of DCM, in2009-2011, we collected1dilated cardiomyopathy pedigree and31sporadic DCM patients. Using PCR and Sanger direct sequencing method, we screened LMNA gene in these patients for more mutations associated with DCM.By screening of LMNA gene in1DCM pedigree patients and31DCM sporadic cases for the mutation, we totally identified8variants,5of8are reported SNPs (rs505058. rs553016、rs74116489、rs4641、rs538089), another3were in non-coding regions, which were unknown variants including c.(-)212t>c、c.*319a>g、c.1698+57g>a, which may be the causative variants for DCM.