A novel missense mutation, p.Phe360Cys, in <scp>FIX</scp> gene results in haemophilia B in a female patient with skewed X‐inactivation

Yang, Chun‐Chen; Yu, Ziqiang; Zhang, W.; Cao, Lijuan; Ouyang, Wanyan; Hu, Fayun; Zhang, P.; Bai, Xia; Ruan, Changgeng

doi:10.1111/hae.13423

Cited by 5 publications

(5 citation statements)

References 9 publications

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“…As a covalent interaction, disulfide bonds play a significant role in protein stability and conformation, as well as protein subunit linkage (Khoo & Norton, 2011). These results suggest that the FIX‐Met394Thr variant may alter the normal physiological function of the FIX protein by disrupting its spatial conformation, consistently with the p.Phe360Cys variant in the previous research (C. Yang et al, 2018).…”

Section: Discussionsupporting

confidence: 88%

“…Hemophilia B (HB) is a rare X‐linked bleeding disorder characterized by a functional deficiency in FIX encoded by the FIX gene ( F9 , MIM:300746). It affects 1 in 30,000 men, and women are usually asymptomatic carriers (Berntorp et al, 2021; Yang et al, 2018). According to the residual FIX activity (FIX: C), HB can be divided into mild (5% to <40% of normal), moderate (1%–5% of normal), and severe (<1% of normal) (Srivastava et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

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Molecular pathogenesis of a novel Met394Thr variant causing hemophilia B

Wang

Shen

et al. 2023

Molec Gen & Gen Med

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Background: Hemophilia B (HB), a rare bleeding disorder, shows X-linked recessive inheritance and is caused by heterogeneous variants in the FIX gene (F9) encoding coagulation factor IX (FIX). This study aimed to investigate the molecular pathogenesis of a novel Met394Thr variant causing HB. Methods:We used Sanger sequencing to analyze F9 sequence variants in members of a Chinese family with moderate HB. Subsequently, we performed in vitro experiments on the identified novel FIX-Met394Thr variant. In addition, we performed bioinformatics analysis of the novel variant. Results:We identified a novel missense variant (c.1181T>C, p.Met394Thr) in a Chinese family with moderate HB in the proband. The proband's mother and grandmother were carriers for the variant. The identified FIX-Met394Thr variant did not affect the transcription of F9 and the synthesis and secretion of FIX protein. The variant may, therefore, affect the physiological function of FIX protein by disrupting its spatial conformation. In addition, another variant (c.88+75A>G) in intron 1 of F9 was identified in the grandmother, which may also affect FIX protein function. Conclusion:We identified FIX-Met394Thr as a novel causative variant of HB.Further understanding of the molecular pathogenesis underlying FIX deficiency may guide novel strategies for precision HB therapy.

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Section: Discussionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Molecular pathogenesis of a novel Met394Thr variant causing hemophilia B

Wang

Shen

et al. 2023

Molec Gen & Gen Med

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“…In addition to X-ALD, XCI serves an important role in other common X-linked recessive diseases. Yang et al ( 23 ) found skewed XCI in a female patient who had a heterozygous missense mutation in the FIX gene and a complete clinical manifestation of moderate hemophilia B was noted. A total of 28% of heterozygous females with FVIII or FIX variants have clinical manifestations and exhibit skewed XCI ( 24 ).…”

Section: Discussionmentioning

confidence: 99%

X‑linked adrenoleukodystrophy caused by maternal ABCD1 mutation and paternal X chromosome inactivation

Lai

2022

Exp Ther Med

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X-linked adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder. It is caused by defects in the ATP-binding cassette subfamily D member 1 (ABCD1) gene, resulting in impaired peroxisomal β-oxidation of very-long-chain fatty acids (VLCFAs). As an X-linked recessive disease, female X-ALD carriers are typically asymptomatic. In the present study, a 7-year-old girl was diagnosed with cerebral ALD. Brain magnetic resonance imaging revealed asymmetric demyelination of bilateral white matter. Plasma VLCFAs level showed a substantial increase. Whole exome and Sanger sequencing revealed an ABCD1 c.919C>T (p.Q307X) heterozygous pathogenic mutation, which was inherited from the asymptomatic mother. X chromosome inactivation (XCI) analysis revealed that the normal paternal X chromosome was almost completely inactivated. Thus, the maternal ABCD1 mutation and paternal XCI were responsible for causing the disease in the patient. XCI may be one reason female X-ALD carriers can be symptomatic.

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“…Due to different numbering of the residues (Human Genome Variation Society vs legacy numbering), the same mutation is referred to as Phe314Leu in a separate report and was associated with a mild bleeding phenotype, similar to that of our patient. Other nucleotide substitutions at the same residue have also been reported resulting in the following amino acid substitutions: Phe360Ile, Phe360Cys, and Phe360Ser [ 13 - 14 ]. Taken together, these reports suggest that substitutions of amino acid residue Phe360 are not well-tolerated, and the variant at this locus was likely the case of our patient’s congenital hemophilia B.…”

Section: Discussionmentioning

confidence: 99%

A Case of Acquired Hemophilia A and Congenital Hemophilia B

Fortier¹,

Pang²,

Amofa-Ho³

et al. 2022

Cureus

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Congenital hemophilia B is a rare, inherited X-linked bleeding disorder caused by a deficiency of factor IX (FIX). Acquired hemophilia A is a rare, acquired bleeding disorder which presents as new onset bleeding in older adults due to the development of autoantibodies against factor VIII (FVIII). This report describes the management of a patient with congenital hemophilia B and acquired hemophilia A. We highlight the limitations in maintaining FVIII levels using factor replacement alone and the need for escalating treatment such as rituximab and prednisone in patients with acquired hemophilia A. This case demonstrates the importance of continuing to pursue alternative diagnoses when existing ones do not explain the full clinical picture and laboratory data is inconclusive.

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A novel missense mutation, p.Phe360Cys, in FIX gene results in haemophilia B in a female patient with skewed X‐inactivation

Cited by 5 publications

References 9 publications

Molecular pathogenesis of a novel Met394Thr variant causing hemophilia B

Molecular pathogenesis of a novel Met394Thr variant causing hemophilia B

X‑linked adrenoleukodystrophy caused by maternal ABCD1 mutation and paternal X chromosome inactivation

A Case of Acquired Hemophilia A and Congenital Hemophilia B

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