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

V. Klaus, T. Vermeulen, B. Minassian, N. Israelian, K. Engel, A. M. Lund, K. Roebrock, E. Christensen, J. Häberle

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Klaus V, Vermeulen T, Minassian B, Israelian N, Engel K, Lund AM, Roebrock K, Christensen E, Häberle J. Highly variable clinical phenotype of carbamylphosphate synthetase 1 deficiency in one family: an effect of allelic variation in gene expression? 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.

Original languageEnglish (US)
Pages (from-to)263-269
Number of pages7
JournalClinical Genetics
Volume76
Issue number3
DOIs
StatePublished - Sep 1 2009

Fingerprint

Ligases
Phenotype
Gene Expression
Mutation
Clone Cells
Alleles
Allelic Imbalance
Hyperammonemia
Confusion
Messenger RNA
Age of Onset
Introns
Haplotypes
Genes
Urea
Organism Cloning
Exons
Diet
Enzymes

Keywords

  • Allelic expression
  • Allelic variation
  • Carbamylphosphate synthetase 1 CPS1
  • Inborn error of metabolism
  • Late-onset urea cycle disorder
  • Neonatal hyperammonemia
  • Regulatory element

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Highly variable clinical phenotype of carbamylphosphate synthetase 1 deficiency in one family : An effect of allelic variation in gene expression? / Klaus, V.; Vermeulen, T.; Minassian, B.; Israelian, N.; Engel, K.; Lund, A. M.; Roebrock, K.; Christensen, E.; Häberle, J.

In: Clinical Genetics, Vol. 76, No. 3, 01.09.2009, p. 263-269.

Research output: Contribution to journalArticle

Klaus, V. ; Vermeulen, T. ; Minassian, B. ; Israelian, N. ; Engel, K. ; Lund, A. M. ; Roebrock, K. ; Christensen, E. ; Häberle, J. / Highly variable clinical phenotype of carbamylphosphate synthetase 1 deficiency in one family : An effect of allelic variation in gene expression?. In: Clinical Genetics. 2009 ; Vol. 76, No. 3. pp. 263-269.
@article{ad10dfcc6c014f43931fc453a74fded0,
title = "Highly variable clinical phenotype of carbamylphosphate synthetase 1 deficiency in one family: An effect of allelic variation in gene expression?",
abstract = "Klaus V, Vermeulen T, Minassian B, Israelian N, Engel K, Lund AM, Roebrock K, Christensen E, H{\"a}berle J. Highly variable clinical phenotype of carbamylphosphate synthetase 1 deficiency in one family: an effect of allelic variation in gene expression? 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.",
keywords = "Allelic expression, Allelic variation, Carbamylphosphate synthetase 1 CPS1, Inborn error of metabolism, Late-onset urea cycle disorder, Neonatal hyperammonemia, Regulatory element",
author = "V. Klaus and T. Vermeulen and B. Minassian and N. Israelian and K. Engel and Lund, {A. M.} and K. Roebrock and E. Christensen and J. H{\"a}berle",
year = "2009",
month = "9",
day = "1",
doi = "10.1111/j.1399-0004.2009.01216.x",
language = "English (US)",
volume = "76",
pages = "263--269",
journal = "Clinical Genetics",
issn = "0009-9163",
publisher = "Wiley-Blackwell",
number = "3",

}

TY - JOUR

T1 - Highly variable clinical phenotype of carbamylphosphate synthetase 1 deficiency in one family

T2 - 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, A. M.

AU - Roebrock, K.

AU - Christensen, E.

AU - Häberle, J.

PY - 2009/9/1

Y1 - 2009/9/1

N2 - Klaus V, Vermeulen T, Minassian B, Israelian N, Engel K, Lund AM, Roebrock K, Christensen E, Häberle J. Highly variable clinical phenotype of carbamylphosphate synthetase 1 deficiency in one family: an effect of allelic variation in gene expression? 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 - Klaus V, Vermeulen T, Minassian B, Israelian N, Engel K, Lund AM, Roebrock K, Christensen E, Häberle J. Highly variable clinical phenotype of carbamylphosphate synthetase 1 deficiency in one family: an effect of allelic variation in gene expression? 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.

KW - Allelic expression

KW - Allelic variation

KW - Carbamylphosphate synthetase 1 CPS1

KW - Inborn error of metabolism

KW - Late-onset urea cycle disorder

KW - Neonatal hyperammonemia

KW - Regulatory element

UR - http://www.scopus.com/inward/record.url?scp=70350151547&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=70350151547&partnerID=8YFLogxK

U2 - 10.1111/j.1399-0004.2009.01216.x

DO - 10.1111/j.1399-0004.2009.01216.x

M3 - Article

C2 - 19793055

AN - SCOPUS:70350151547

VL - 76

SP - 263

EP - 269

JO - Clinical Genetics

JF - Clinical Genetics

SN - 0009-9163

IS - 3

ER -