Novel splice site mutations in the gamma glutamyl carboxylase gene in a child with congenital combined deficiency of the vitamin K‐dependent coagulation factors (VKCFD)

Titapiwatanakun, Ruetima; Rodriguez, Vilmarie; Middha, Sumit; Dukek, Brian A.; Pruthi, Rajiv K.

doi:10.1002/pbc.22011

Cited by 7 publications

(5 citation statements)

References 22 publications

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“…One exception is a 14 bp deletion in intron 1, which is supposed to be involved in the protein expression [13]. VKCFD type 1 has been shown to result from compound heterozygosity of missense mutations in the GGCX gene [19,25-27]. VKOR was identified 34 years ago [28] but its biochemistry has been difficult to understand because of refractoriness to purification.…”

Section: Etiopathogenesismentioning

confidence: 99%

Hereditary combined deficiency of the vitamin K-dependent clotting factors

Napolitano

Mariani

Lapecorella

2010

Orphanet J Rare Dis

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Hereditary combined vitamin K-dependent clotting factors deficiency (VKCFD) is a rare congenital bleeding disorder resulting from variably decreased levels of coagulation factors II, VII, IX and X as well as natural anticoagulants protein C, protein S and protein Z. The spectrum of bleeding symptoms ranges from mild to severe with onset in the neonatal period in severe cases. The bleeding symptoms are often life-threatening, occur both spontaneously and in a surgical setting, and usually involve the skin and mucosae. A range of non-haemostatic symptoms are often present, including developmental and skeletal anomalies. VKCFD is an autosomal recessive disorder caused by mutations in the genes of either gamma-glutamyl carboxylase or vitamin K2,3-epoxide reductase complex. These two proteins are necessary for gamma-carboxylation, a post-synthetic modification that allows coagulation proteins to display their proper function. The developmental and skeletal anomalies seen in VKCFD are the result of defective gamma-carboxylation of a number of non-haemostatic proteins. Diagnostic differentiation from other conditions, both congenital and acquired, is mandatory and genotype analysis is needed to confirm the defect. Vitamin K administration is the mainstay of therapy in VKCFD, with plasma supplementation during surgery or severe bleeding episodes. In addition, prothrombin complex concentrates and combination therapy with recombinant activated FVII and vitamin K supplementation may constitute alternative treatment options. The overall prognosis is good and with the availability of several effective therapeutic options, VKCFD has only a small impact on the quality of life of affected patients.

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Section: Etiopathogenesismentioning

confidence: 99%

Hereditary combined deficiency of the vitamin K-dependent clotting factors

Napolitano

Mariani

Lapecorella

2010

Orphanet J Rare Dis

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“…The disease was coined VK-dependent clotting factor deficiency-1 (VKCFD1, OMIM#277450), an autosomal recessive disorder, characterized by a mild to severe bleeding tendency and a moderate predisposition to thrombotic events [13,20]. VKCFD1 was shown to be associated with skeletal (midfacial hypoplasia, reduced bone mass, chondrodysplasia punctata) or cardiac abnormalities (patent ductus arteriosus Botalli, septal closure defects) in some patients [13,21,22,23,24,25,26,27,28,29,30]. Next to VKCFD1, a second autosomal recessive coagulation factor deficiency exists, VKCFD2 (OMIM#607473), caused by VKORC1 (vitamin K epoxide reductase complex, subunit 1; OMIM*608547) mutations and is also characterized by a deficiency of all VK-dependent clotting factors.…”

Section: Introductionmentioning

confidence: 99%

GGCX-Associated Phenotypes: An Overview in Search of Genotype-Phenotype Correlations

Vilder

Debacker

Vanakker

2017

IJMS

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Gamma-carboxylation, performed by gamma-glutamyl carboxylase (GGCX), is an enzymatic process essential for activating vitamin K-dependent proteins (VKDP) with important functions in various biological processes. Mutations in the encoding GGCX gene are associated with multiple phenotypes, amongst which vitamin K-dependent coagulation factor deficiency (VKCFD1) is best known. Other patients have skin, eye, heart or bone manifestations. As genotype–phenotype correlations were never described, literature was systematically reviewed in search of patients with at least one GGCX mutation with a phenotypic description, resulting in a case series of 47 patients. Though this number was too low for statistically valid correlations—a frequent problem in orphan diseases—we demonstrate the crucial role of the horizontally transferred transmembrane domain in developing cardiac and bone manifestations. Moreover, natural history suggests ageing as the principal determinant to develop skin and eye symptoms. VKCFD1 symptoms seemed more severe in patients with both mutations in the same protein domain, though this could not be linked to a more perturbed coagulation factor function. Finally, distinct GGCX functional domains might be dedicated to carboxylation of very specific VKDP. In conclusion, this systematic review suggests that there indeed may be genotype–phenotype correlations for GGCX-related phenotypes, which can guide patient counseling and management.

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“…A very similar VKCFD patient phenotype is also reported for GGCX mutations leading to type 1 deficiency. In some VKCFD1 patients, a phenotype similar to warfarin embryopathy is additionally found that includes facial hypoplasia and epiphyseal stippling, similar to a chondrodysplasia puncta phenotype, and also a pseudoxanthoma elasticum-like phenotype (39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51). These additional non-bleeding phenotypes are not common for VKCFD2 patients.…”

Section: Diagnosismentioning

confidence: 99%

“…Individuals that are heterozygous for VKORC1 : p.Arg98Trp normally develop no phenotype and exhibit activities for the VKD coagulation factors in normal range. In contrast, there are many more mutations in the GGCX gene reported to cause VKCFD1 in heterozygous, homozygous as well as compound heterozygous form (currently 27 mutations known) (39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51).…”

Section: Diagnosismentioning

confidence: 99%

“…It is curious that only VKORC1 : p.Arg98Trp causes reduced VKOR activity leading to VKCFD2 and that all other mutations in VKORC1 are reported to cause VKA resistance (55,56). In comparison, there are several mutations in GGCX known to cause VKCFD1 (39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51). Why then is VKORC1 : p.Arg98Trp the only mutation causing VKCFD2 and what is the underlying molecular mechanism?…”

Section: Molecular Mechanism Of Vkcfd2mentioning

confidence: 99%

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VKCFD2 – from clinical phenotype to molecular mechanism

Czogalla¹,

Watzka²,

Oldenburg³

2016

Hamostaseologie

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SummaryVitamin K 2,3-epoxide reductase complex, subunit 1 (VKORC1) is an enzyme essential for the vitamin K cycle. VKORC1 catalyses the reduction of vitamin K 2,3-epoxide to the quinone form of vitamin K and further to vitamin K hydroquinone. The generated vitamin K hydroquinone serves as substrate for the enzyme γ-glutamyl-carboxylase which modifies all vitamin K-dependent proteins, allowing them to bind calcium ions necessary for physiological activity. Vitamin K-dependent proteins include the coagulation factors FII, FVII, FIX, FX, and proteins C, S und Z. Insufficient VKORC1 enzyme activity results in deficiency of the vitamin K-dependent clotting factors leading to haemorrhagic disorders. This phenotype is known as vitamin K clotting factor deficiency type 2 (VKCFD2). Worldwide, only four families of independent origin have been reported with this rare bleeding disorder. Affected family members carry the mutation VKORC1:p.Arg98Trp in homozygous form, the only mutation found so far to be associated with VKCFD2. Now, ten years after the identification of the VKORC1 gene, the molecular pathomechanism of VKCFD2 has been clarified. The Arg98Trp mutation disrupts an ER retention motif of VKORC1 leading to mislocalisation of the protein to outside the endoplasmatic reticulum. In this review, we summarize the clinical data, diagnosis, therapy and molecular patho -mechanism of VKCFD2.

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Novel splice site mutations in the gamma glutamyl carboxylase gene in a child with congenital combined deficiency of the vitamin K‐dependent coagulation factors (VKCFD)

Cited by 7 publications

References 22 publications

Hereditary combined deficiency of the vitamin K-dependent clotting factors

Hereditary combined deficiency of the vitamin K-dependent clotting factors

GGCX-Associated Phenotypes: An Overview in Search of Genotype-Phenotype Correlations

VKCFD2 – from clinical phenotype to molecular mechanism

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