IKBKAP mRNA in peripheral blood leukocytes: a molecular marker of gene expression and splicing in familial dysautonomia.
The common familial dysautonomia (FD) mutation results in tissue specific mis-splicing with reduced amount of wild-type (WT) IkappaB kinase associated protein gene (IKBKAP) mRNA and ELP1. ELP1 is a subunit of Elongator, formerly called the IkappaB kinase associated protein (IKAP) protein. We measured IKBKAP mRNA in peripheral blood leukocytes to determine whether FD subjects and carriers have characteristic levels. Estimated mean IKBKAP mRNA levels, measured by quantitative PCR and expressed as amount relative to the noncarrier average, were significantly different for the two groups when not adjusted for age and sex (p < 0.001): FD subjects 0.23, 95% confidence interval (CI) (0.19, 0.28); carriers 0.58, 95% CI (0.50, 0.68); or adjusted for age and sex (p < 0.001): FD subjects 0.21, 95% CI (0.16, 0.26); carriers 0.66, 95% CI (0.55, 0.79). Comparison of IKBKAP mRNA levels of the 22 FD subjects and their related carriers showed a strong correlation, providing evidence for genetic control of splicing efficiency. IKBKAP mRNA levels were not higher in those subjects using tocotrienols or epigallocatechin gallate. Levels of IKBKAP mRNA in peripheral blood leukocytes can be used to assess molecular response to therapies aimed at enhancing exon 20 inclusion and increasing cellular levels of ELP1/IKAP.
Gold-von Simson
Gabrielle
G
Department of Pediatrics, New York University School of Medicine, New York, New York 10016, USA. gold01@med.nyu.edu
Leyne
Maire
M
Mull
James
J
Rolnitzky
Linda M
LM
Goldberg
Judith D
JD
Berlin
Dena
D
Axelrod
Felicia B
FB
Slaugenhaupt
Susan A
SA
D000293:Adolescent; D000328:Adult; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D004402:Dysautonomia, Familial / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D006579:Heterozygote; D006801:Humans; D007962:Leukocytes / Q000166:cytology*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D015233:Models, Statistical; D009154:Mutation; D035602:Transcriptional Elongation Factors
D002352:Carrier Proteins; C114720:Elp1 protein, human; D035602:Transcriptional Elongation Factors