Hereditary angioedema: The mutation spectrum ofSERPING1/C1NHin a large Spanish cohort

Abstract

Hereditary angioedema (HAE) is a disease caused by defects in the C1 inhibitor gene (SERPING1/C1NH). We screened the entire C1NH gene for mutations in a large series of 87 Spanish families (77 with type I, and 10 with type II HAE) by SSCP, sequencing, Southern blotting, and quantitative multiplex PCR of short fluorescent fragments (QMPSF), and we characterized several defects at the mRNA level. We found large rearrangements in 13 families, and point mutations or microdeletions/insertions in 74 families. The 13 large rearrangements included nine exon deletions, of which at least eight were distinct, two were distinct exon duplications, and two were rearrangements whose precise nature could not be determined. We confirmed that exon 4 is particularly prone to rearrangements. Thirty-six mutations were unreported, and included 10 microdeletions/insertions, 10 missense, five nonsense, eight splicing, and three splicing or missense mutations. Moreover, we detected six novel uncharacterized sequence variants (USV). RT-PCR studies showed that in addition to several intronic splice site mutations tested, the exonic mutations c.882C>G and c.884T>G, located near the 3' end of exon 5, also produced exon skipping. This is the first evidence of SERPING1/C1NH mutations in coding regions that differ from the canonical splice sites that affect splicing, which suggests the presence of an exonic splicing enhancer (ESE) in exon 5.

Successful allogeneic cord blood transplantation in a patient with Evans syndrome leads to correction of hereditary angioedema type I as secondary effect

“…We detected a well-known heterozygous transition of the nucleotides guanine to adenine in the conserved donor splice site of exon/intron3 in the SERPING1 gene defined as 550 þ 5G4A, which was already published by Roche et al 8 The mutation was disclosed in the index patient, his mother and his uncle (Figure 1). The index patient's mutation was clearly detected in genomic DNA extracted from blood provided for analysis before cord blood transplantation (Figure 1a), whereas the mutation disappeared completely in DNA extracted from blood retained from the index patient 5 years after cord blood transplantation (Figure 1b).…”

The Turkish Hereditary Angioedema Pilot Study (TURHAPS): The First Turkish Series of Hereditary Angioedema

“…The 5 known mutations were heterozygous 36_37 delAG 1 and heterozygous p.G162R 1 in exon 3, heterozygous p.W243X 1 in exon 5, heterozygous p.M303T 1 in exon 6 and heterozygous p.Q370X 1 in exon 7 [7,8,9]. All were familial occurrences.…”

Secretome of Primary Cultures of Human Adipose-derived Stem Cells

“…The C1 inhibitor is a glycosylated serum protein first identified based on its ability to block the activation of the first component of the complement pathway (50). Mutations altering the inhibitory function of the protein are associated with hereditary angioneurotic edema, a rare but life-threatening autosomal dominant disorder that can cause acute airway obstruction due to edematous changes in the soft tissue of the throat (51,52). Curiously the C1 inhibitor is a cleavage target of the human immunodeficiency virus (type 1) protease and, consistent with this observation, serum from human immunodeficiency virus-infected patients inhibits activation of the classical complement pathway (53,54).…”