A novel mutation in the third extracellular domain of the tumor necrosis factor receptor 1 in a Finnish family with autosomal-dominant recurrent fever.
OBJECTIVE
To investigate the presence of TRAPS (tumor necrosis factor receptor-associated periodic syndrome), which is a recently defined, dominantly inherited autoinflammatory syndrome caused by mutations in the tumor necrosis factor receptor superfamily 1A gene (TNFRSF1A, CD120a), in a Finnish family with recurrent fever.


METHODS
The TNFRSF1A gene was sequenced in both affected and unaffected family members. Flow cytometry and enzyme-linked immunosorbent assay analyses were used to assess membrane expression and serum levels of the TNFRSF1A protein, respectively.


RESULTS
A missense mutation in exon 4, located in the third extracellular domain of TNFRSF1A and resulting in an amino acid substitution (F112I) close to a conserved cysteine, was found in all 4 affected family members and in 1 asymptomatic individual. The mutation was clearly associated with low levels of soluble TNFRSF1A as well as with the clinical symptoms of recurrent fever and abdominal pain. Impaired shedding of TNFRSF1A after phorbol myristate acetate stimulation was detected in blood granulocytes and monocytes from the 3 adult family members with the mutation, but in the child bearing the mutation and showing clinical symptoms of recent onset, the shedding defect was less marked.


CONCLUSIONS
TRAPS should be suspected in any patient who presents with a history of intermittent fever accompanied by unexplained abdominal pain, arthritis, or skin rash, particularly in the presence of a family history of such symptoms. Screening for low serum levels of soluble TNFRSF1A identifies individuals who are likely to have TNFRSF1A mutations.
Nevala
Hanna
H
Helsinki University Central Hospital, Helsinki, Finland.
Karenko
Leena
L
Stjernberg
Susanna
S
Raatikainen
Maria
M
Suomalainen
Hanna
H
Lagerstedt
Anssi
A
Rauta
Jenita
J
McDermott
Michael F
MF
Peterson
Pärt
P
Pettersson
Tom
T
Ranki
Annamari
A
D000328:Adult; D015703:Antigens, CD / Q000032:analysis / Q000737:chemistry / Q000235:genetics*; D005110:Extracellular Space / Q000737:chemistry; D010505:Familial Mediterranean Fever / Q000235:genetics*; D005192:Family Health; D005260:Female; D005387:Finland; D005434:Flow Cytometry; D005799:Genes, Dominant; D005838:Genotype; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D017434:Protein Structure, Tertiary; D018124:Receptors, Tumor Necrosis Factor / Q000032:analysis / Q000737:chemistry / Q000235:genetics*; D047888:Receptors, Tumor Necrosis Factor, Type I; D012008:Recurrence
D015703:Antigens, CD; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I