PMID- 10602775
OWN - NLM
STAT- MEDLINE
DCOM- 20000120
LR  - 20181113
IS  - 1076-1551 (Print)
IS  - 1076-1551 (Linking)
VI  - 5
IP  - 10
DP  - 1999 Oct
TI  - Identification and expression of mutations in the hydroxymethylbilane synthase
      gene causing acute intermittent porphyria (AIP).
PG  - 664-71
AB  - BACKGROUND: Acute intermittent porphyria (AIP), an autosomal dominant inborn
      error, results from the half-normal activity of the heme biosynthetic enzyme
      hydroxymethylbilane synthase (EC 4.3.1.8; HMB-synthase). This disease is
      characterized by acute, life-threatening neurologic attacks that are precipitated
      by various drugs, hormones, and other factors. The enzymatic and/or biochemical
      diagnosis of AIP heterozygotes is problematic; therefore, efforts have focused on
      the identification of HMB-synthase mutations so that heterozygotes can be
      identified and educated to avoid the precipitating factors. In Spain, the
      occurrence of AIP has been reported, but the nature of the HMB-synthase mutations
      causing AIP in Spanish families has not been investigated. Molecular analysis was
      therefore undertaken in nine unrelated Spanish AIP patients. MATERIALS AND
      METHODS: Genomic DNA was isolated from affected probands and family members of
      nine unrelated Spanish families with AIP. The HMB-synthase gene was amplified by 
      long-range PCR and the nucleotide sequence of each exon was determined by cycle
      sequencing. RESULTS: Three new mutations, a missense, M212V; a single base
      insertion, g4715insT; and a deletion/insertion, g7902ACT-->G, as well as five
      previously reported mutations (G111R, R116W, R149X R167W, and R173W) were
      detected in the Spanish probands. Expression of the novel missense mutation M212V
      in E. coli revealed that the mutation was causative, having <2% residual
      activity. CONCLUSIONS: These studies identified the first mutations in the
      HMB-synthase gene causing AIP in Spanish patients. Three of the mutations were
      novel, while five previously reported lesions were found in six Spanish families.
      These findings enable accurate identification and counseling of presymptomatic
      carriers in these nine unrelated Spanish AIP families and further demonstrate the
      genetic heterogeneity of mutations causing AIP.
FAU - Solis, C
AU  - Solis C
AD  - Biochemical Laboratory, University Hospital La Paz, Madrid, Spain.
FAU - Lopez-Echaniz, I
AU  - Lopez-Echaniz I
FAU - Sefarty-Graneda, D
AU  - Sefarty-Graneda D
FAU - Astrin, K H
AU  - Astrin KH
FAU - Desnick, R J
AU  - Desnick RJ
LA  - eng
GR  - 5 M01 RR00071/RR/NCRR NIH HHS/United States
GR  - 5 P30 HD28822/HD/NICHD NIH HHS/United States
GR  - 5 R01 DK26824/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - England
TA  - Mol Med
JT  - Molecular medicine (Cambridge, Mass.)
JID - 9501023
RN  - 0 (DNA Primers)
RN  - EC 2.5.1.61 (Hydroxymethylbilane Synthase)
SB  - IM
MH  - Amino Acid Sequence
MH  - Base Sequence
MH  - CpG Islands
MH  - DNA Primers
MH  - Female
MH  - Humans
MH  - Hydroxymethylbilane Synthase/*genetics
MH  - Male
MH  - *Mutation, Missense
MH  - Pedigree
MH  - Polymerase Chain Reaction
MH  - Porphyria, Acute Intermittent/*genetics
PMC - PMC2230478
EDAT- 1999/12/22 00:00
MHDA- 1999/12/22 00:01
CRDT- 1999/12/22 00:00
PHST- 1999/12/22 00:00 [pubmed]
PHST- 1999/12/22 00:01 [medline]
PHST- 1999/12/22 00:00 [entrez]
AID - 0193 [pii]
PST - ppublish
SO  - Mol Med. 1999 Oct;5(10):664-71.