Severe protein C deficiency from compound heterozygous mutations in the PROC gene in two Korean adult patients

Congenital protein C deficiency presenting as purpura fulminans is a rare condition in neonates. It is a disorder with autosomal recessive inheritance and is caused by homozygous or compound heterozygous mutations in PROC gene. The authors report a case of autosomal homozygous PROC gene transversion mutation in a newborn baby born to third degree consanguineous parents who presented as purpura fulminans at birth. She had almost undetectable protein C levels. As protein C concentrate was not readily available, she was managed with low molecular weight heparin along with fresh frozen plasma. Despite our best efforts, baby succumbed to her illness on day 21 of life. Autosomal recessive protein C deficiency should always be sought as an explanation for thrombotic disorders in the newborn with manifestations of disseminated intravascular coagulation.

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Two novel compound heterozygous mutations associated with types I and II protein C deficiency with unusual phenotypes

Thrombosis Research ◽

10.1016/j.thromres.2016.08.005 ◽

2016 ◽

Vol 145 ◽

pp. 93-99 ◽

Cited By ~ 2

Author(s):

Ming-yang Deng ◽

Zi-xian Liu ◽

Hai-fan Huang ◽

Yong-heng Chen ◽

Yu-jiao Luo ◽

...

Keyword(s):

Protein C ◽

Compound Heterozygous ◽

Protein C Deficiency ◽

Compound Heterozygous Mutations

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Protein C deficiency; PROC gene variants in a Danish population

Thrombosis Research ◽

10.1016/j.thromres.2019.11.027 ◽

2020 ◽

Vol 185 ◽

pp. 153-159

Author(s):

Anne Winther-Larsen ◽

Alisa D. Kjaergaard ◽

Ole H. Larsen ◽

Anne-Mette Hvas ◽

Peter H. Nissen

Keyword(s):

Protein C ◽

Gene Variants ◽

Danish Population ◽

Protein C Deficiency ◽

Proc Gene

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A Compound Heterozygous Protein C Deficiency with a Single Nucleotide G Deletion Encoding Gly-381 and an Amino Acid Substitution of Lys for Gla-26

Thrombosis and Haemostasis ◽

10.1055/s-0038-1649641 ◽

1993 ◽

Vol 70 (04) ◽

pp. 636-641 ◽

Cited By ~ 12

Author(s):

Masaru Ido ◽

Michiaki Ohiwa ◽

Tatsuya Hayashi ◽

Junji Nishioka ◽

Tsuyoshi Hatada ◽

...

Keyword(s):

Amino Acid ◽

Protein C ◽

Purpura Fulminans ◽

Male Infant ◽

Compound Heterozygous ◽

Dependent Manner ◽

Protein C Deficiency ◽

Single Nucleotide ◽

Nucleotide Mutation ◽

Gla Domain

SummaryWe report genetic abnormalities of protein C gene in a male infant who developed neonatal purpura fulminans. DNA-sequence analysis of all exons in protein C gene in this family revealed two mutations. The first abnormality, derived from the mother, was a deletion of one of four consecutive G at nucleotide number 10758 in exon IX which would result in a frame shift mutation and completely change amino acid sequence from Gly381 in the carboxyl-terminal region of protein C. The second abnormality, derived from the father, was a single nucleotide mutation from G to A in the codon (GAG to AAG) at nucleotide number 2977 in exon III, which would result in a substitution of Lys for γ-carboxyglutamic acid (Gla)26. This change would be responsible for the reduced immunological protein C levels of the patient and the father, estimated by a monoclonal antibody which recognizes the Gla-domain in a Ca2+-dependent manner (3.8% and 57%, respectively). Partially purified abnormal protein C from the father’s plasma showed a normal amidolytic activity and a change in the electrophoretic mobility. We detected the above mutations in his family members using two methods; one was a creation of new restriction enzyme sites using mutagenic primers and the other was single nucleotide primer extension. Both methods are rapid and useful for the diagnosis of prenatal protein C abnormalities.

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Acroangiodermatitis of Mali in Protein C Deficiency Due to a Novel PROC Gene Mutation

American Journal of Dermatopathology ◽

10.1097/dad.0b013e3182169528 ◽

2012 ◽

Vol 34 (2) ◽

pp. e19-e21 ◽

Cited By ~ 1

Author(s):

Aaron Wei-Min Tan ◽

Joyce Siong-See Lee ◽

Zacharias A. D. Pramono ◽

Wei-Sheng Chong

Keyword(s):

Gene Mutation ◽

Protein C ◽

Protein C Deficiency ◽

Proc Gene

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Three novel PROC gene lesions causing protein C deficiency

Clinical Genetics ◽

10.1111/j.1399-0004.1998.tb04290.x ◽

2008 ◽

Vol 54 (3) ◽

pp. 231-233 ◽

Cited By ~ 2

Author(s):

PJ Hallam ◽

P. Mannucci ◽

A. Tripodi ◽

D. Bevan ◽

B. Lawsen ◽

...

Keyword(s):

Protein C ◽

Protein C Deficiency ◽

Proc Gene

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A novel frameshift mutation Gly239Serfs*8 in the PROC gene results in protein C deficiency in a Korean patient

Annals of Hematology ◽

10.1007/s00277-012-1484-4 ◽

2012 ◽

Vol 91 (11) ◽

pp. 1829-1830 ◽

Cited By ~ 1

Author(s):

Sang Hyuk Park ◽

Seongsoo Jang ◽

Hye-Kyung Yang ◽

Hyoeun Shim ◽

Chan-Jeoung Park ◽

...

Keyword(s):

Protein C ◽

Frameshift Mutation ◽

Protein C Deficiency ◽

Korean Patient ◽

Proc Gene

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Compound Heterozygous Protein C Deficiency Caused by Two Mutations, Arg-178 to Gin and Cys-331 to Arg, Leading to Impaired Secretion of Mutant Protein C

Thrombosis and Haemostasis ◽

10.1055/s-0038-1648967 ◽

1994 ◽

Vol 72 (06) ◽

pp. 814-818 ◽

Cited By ~ 11

Author(s):

Yuichi Sugahara ◽

Osamu Miura ◽

Shinsaku Hirosawa ◽

Nobuo Aoki

Keyword(s):

Disulfide Bond ◽

Protein C ◽

Catalytic Domain ◽

Point Mutations ◽

Expression Vectors ◽

Compound Heterozygous ◽

Protein C Deficiency ◽

Peptide Cleavage ◽

Mutant Proteins ◽

Heterozygous Protein C Deficiency

SummaryThe protein C gene in a patient apparently homozygous for protein C deficiency was analyzed. Two different point mutations, each located in a different allele, were detected to reveal that the patient is a compound heterozygote. Mutation of Arg-178 (CGG) to Gin (CAG) [mutation I] was detected in exon VII, in the vicinity of activation peptide cleavage site by thrombin. Mutation of Cys-331 (TGC) to Arg (CGC) [mutation II] was found in exon IX, at one of the sites involved in disulfide bond formation in the catalytic domain of the heavy chain. The alteration of Cys-331 to Arg disables the formation of the disulfide bond and would alter the protein conformation. Transient expression assays using COS-7 cells transfected with protein C expression vectors containing each one of these two mutations suggested that each of the two mutations would lead to the protein C deficiency by an impairment of secretion of the respective mutant proteins.

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Severe perinatal thrombosis in double and triple heterozygous offspring of a family segregating two independent protein S mutations and a protein C mutation

Blood ◽

10.1182/blood.v87.9.3731.bloodjournal8793731 ◽

1996 ◽

Vol 87 (9) ◽

pp. 3731-3737 ◽

Cited By ~ 20

Author(s):

CJ Formstone ◽

PJ Hallam ◽

EG Tuddenham ◽

J Voke ◽

M Layton ◽

...

Keyword(s):

Protein C ◽

Antenatal Diagnosis ◽

Umbilical Vein ◽

Molecular Genetic ◽

Protein S ◽

Maternal Circulation ◽

Protein C Deficiency ◽

Genotypic Analysis ◽

The Family ◽

Proc Gene

Molecular genetic and phenotypic analyses were performed in a highly unusual case of combined protein S and protein C deficiency manifesting in a family in which a child had died perinatally from renal vein thrombosis. Antenatal diagnosis in a second pregnancy was initially performed by indirect restriction fragment length polymorphism (RFLP) tracking using a neutral dimorphism within the PROS gene and served to exclude severe protein S deficiency. Am umbilical vein blood sample at 22 weeks gestation showed isolated protein C deficiency. This pregnancy proceeded to a full-term delivery without thrombotic complications. Molecular genetic analysis of the PROC and PROS gene segregating in the family then yielded one PROC gene lesion in the father and two PROS gene lesions, one in each parent. These lesions were shown to segregate with the respective deficiency states through the family pedigree. Analysis of DNA from paraffin-embedded liver tissue taken from the deceased child showed the presence of both PROS mutations, as well as the PROC mutation. Genotypic analysis of the second child showed a PROC mutation, but neither PROS mutation consistent with its possession of normal protein S levels and a low/borderline protein C level. Antenatal diagnosis was then performed in a third pregnancy by direct mutation detection. However, although the fetus carried only the paternal PROS and PROC gene lesions, the child developed renal thrombosis in utero. It may be that a further genetic lesion at a third locus still remains to be defined. Alternatively, the intrauterine development of thrombosis in this infant could have been caused, at least in part by a transplacental thrombotic stimulus arising in the protein S-deficient maternal circulation. This analysis may, therefore, serve as a warning against extrapolating too readily from genotype to phenotype in families with a complex thrombotic disorder.

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