Highly variable clinical phenotype of carbamylphosphate synthetase 1 deficiency in one family: an effect of allelic variation in gene expression?

TY - JOUR

T1 - Highly variable clinical phenotype of carbamylphosphate synthetase 1 deficiency in one family: an effect of allelic variation in gene expression?

AU - Klaus, V

AU - Vermeulen, T

AU - Minassian, B

AU - Israelian, N

AU - Engel, K

AU - Lund, Allan Meldgaard

AU - Roebrock, K

AU - Christensen, E

AU - Häberle, J

N1 - Keywords: Alleles; Base Sequence; Carbamoyl-Phosphate Synthase I Deficiency Disease; Child; Clone Cells; Cloning, Molecular; DNA, Complementary; Electrophoresis, Agar Gel; Enhancer Elements, Genetic; Exons; Family; Female; Gene Expression Regulation; Genetic Variation; Haplotypes; Humans; Male; Middle Aged; Molecular Sequence Data; Pedigree; Phenotype

PY - 2009

Y1 - 2009

N2 - Deficiency of the urea cycle enzyme carbamylphosphate synthetase 1 (CPS1) causes hyperammonemia with a vast range of clinical severity from neonatal onset with early lethality to onset after age 40 with rare episodes of hyperammonemic confusion. The cause for this variability is not understood. We report two patients from one family with highly divergent clinical course, one presenting neonatally with a fatal form and the other at age 45 with benign diet-responsive disease. The patients are compound heterozygous for two mutations of the CPS1 gene, c.3558 + 1G > C and c.4101 + 2T > C. The haplotypes containing each mutation are identical between the two patients, as are the sequences of CPS1 exons and flanking introns. Transcriptional experiments show that the abnormal CPS1 transcripts generated by both mutations are identical in these two patients. We characterize promoter and enhancer sequences of the CPS1 gene and find also in these regions no sequence differences between patients. Finally, we perform cloning experiments and find that in the neonatal-onset case, clones of messenger RNA (mRNA) expressed from the allele carrying the c.4101 + 2T > C mutation are threefold more than clones of mRNA from the allele with the c.3558 + 1G > C mutation, whereas in the adult-onset case the two types of clones are equal, indicating skewed expression towards the c.4101 + 2T > C allele in the neonatal case. Although we are yet to understand the mechanism of this differential expression, our work suggests that allelic imbalance may explain clinical variability in CPS1 deficiency in some families.

AB - Deficiency of the urea cycle enzyme carbamylphosphate synthetase 1 (CPS1) causes hyperammonemia with a vast range of clinical severity from neonatal onset with early lethality to onset after age 40 with rare episodes of hyperammonemic confusion. The cause for this variability is not understood. We report two patients from one family with highly divergent clinical course, one presenting neonatally with a fatal form and the other at age 45 with benign diet-responsive disease. The patients are compound heterozygous for two mutations of the CPS1 gene, c.3558 + 1G > C and c.4101 + 2T > C. The haplotypes containing each mutation are identical between the two patients, as are the sequences of CPS1 exons and flanking introns. Transcriptional experiments show that the abnormal CPS1 transcripts generated by both mutations are identical in these two patients. We characterize promoter and enhancer sequences of the CPS1 gene and find also in these regions no sequence differences between patients. Finally, we perform cloning experiments and find that in the neonatal-onset case, clones of messenger RNA (mRNA) expressed from the allele carrying the c.4101 + 2T > C mutation are threefold more than clones of mRNA from the allele with the c.3558 + 1G > C mutation, whereas in the adult-onset case the two types of clones are equal, indicating skewed expression towards the c.4101 + 2T > C allele in the neonatal case. Although we are yet to understand the mechanism of this differential expression, our work suggests that allelic imbalance may explain clinical variability in CPS1 deficiency in some families.

U2 - 10.1111/j.1399-0004.2009.01216.x

DO - 10.1111/j.1399-0004.2009.01216.x

M3 - Journal article

C2 - 19793055

SN - 0009-9163

VL - 76

SP - 263

EP - 269

JO - Clinical Genetics

JF - Clinical Genetics

IS - 3

ER -