Severe factor VII deficiency with recurrent intracranial haemorrhages owing to double heterozygosity for a splice site mutation of an IVS4 and a novel nonsense mutation in exon 8 (Gln211-->Term).
Genetic analysis of a 10-month-old Japanese baby boy with recurrent intrathoracic bleeding, cerebral haemorrhages and gastrointestinal bleeding secondary to severe factor VII (FVII) deficiency revealed evidence of two distinct mutations of FVII: a splice site mutation of G-->A at nucleotide 6071 in the IVS4 splice site and a novel nonsense mutation (Gln211-->Term) in exon 8. His bleeding was difficult to control without prophylactic infusion of FVII. We detected a heterozygous splice site mutation of the IVS4 in his mother and a heterozygous nonsense mutation in exon 8 (Gln211-->Term) in his father. The parents' FVII levels are both 50% of normal controls. The FVII:C in plasma from the proband was < 1.5% of normal controls. FVII:antigen (Ag) was < 1% of normal controls, using a monoclonal antibody (mAb) hVII-B101/1 that specifically reacts with FVII epidermal growth factor 1 (EGF-1), and 5% of normal controls, using a rabbit polyclonal antibody against human FVII. After immunoadsorption with mAb hVII-B101/B1-Sepharose 4B, FVII levels of both the proband and his mother were 5% of normal controls; after immunoadsorption the FVII levels of normal subjects were < 1%. We hypothesize that secretion of a small amount of dysfunctional FVII lacking EGF-1 into the circulation accounts for this observation.
Takamiya
O
O
Department of Medical Technology, School of Allied Medical Sciences, Shinshu University, Asahi, Japan. itosamu@gipac.shinshu-u.ac.jp
Okimoto
Y
Y
D018389:Codon, Nonsense; D004815:Epidermal Growth Factor / Q000235:genetics*; D005091:Exons; D005167:Factor VII / Q000235:genetics*; D005168:Factor VII Deficiency / Q000150:complications* / Q000235:genetics*; D005260:Female; D006579:Heterozygote; D006801:Humans; D007223:Infant; D020300:Intracranial Hemorrhages / Q000209:etiology* / Q000235:genetics; D008297:Male; D022821:RNA Splice Sites / Q000235:genetics; D012008:Recurrence
D018389:Codon, Nonsense; D022821:RNA Splice Sites; D004815:Epidermal Growth Factor; D005167:Factor VII