PMID- 10494093
OWN - NLM
STAT- MEDLINE
DCOM- 19991105
LR  - 20071114
IS  - 0148-7299 (Print)
IS  - 0148-7299 (Linking)
VI  - 86
IP  - 4
DP  - 1999 Oct 8
TI  - Identification and characterization of hydroxymethylbilane synthase mutations
      causing acute intermittent porphyria: evidence for an ancestral founder of the
      common G111R mutation.
PG  - 366-75
AB  - Acute intermittent porphyria (AIP), the most common hepatic porphyria, results
      from the half-normal activity of hydroxymethylbilane synthase (HMB-synthase; EC
      4.3.1.8), the third enzyme in the heme biosynthetic pathway. Because
      life-threatening acute neurologic attacks of this autosomal dominant disease are 
      triggered by various ecogenic factors (e.g., certain drugs, hormones, alcohol,
      and starvation), efforts have been directed to identify and counsel
      presymptomatic heterozygotes in affected families to avoid the precipitating
      factors. Thus, to determine the nature of the mutations causing AIP in 26
      unrelated enzyme-confirmed patients from Argentina, a long-range polymerase chain
      reaction method was developed to amplify the entire 10-kb gene in two fragments
      for efficient cycle sequencing and mutation detection. Eight new mutations were
      identified including two missense mutations (Q34P and G335S), four small
      deletions (728delCT, 815delAGGA, 948delA, and 985del12), a single base insertion 
      (666insA), and a splice site mutation (IVS12(+1)). In addition, five previously
      reported mutations (G111R, R173W, Q204X, R201W, and 913insC) were detected.
      Notably, G111R was identified in 12 of the 26 (46%) presumably unrelated
      propositi; however, haplotype analysis with intragenic and flanking markers
      indicated an ancestral founder. Expression of the two new missense mutations
      (Q34P and G335S) in f1 E. coli resulted in 2.5% or less of the normal expressed
      enzyme, confirming their defective function. Thus, eight new and five previously 
      reported HMB-synthase mutations, including a common lesion, were detected,
      permitting accurate identification and counseling of presymptomatic carriers in
      these 26 unrelated Argentinean AIP families with this dominant porphyria.
CI  - Copyright 1999 Wiley-Liss, Inc.
FAU - De Siervi, A
AU  - De Siervi A
AD  - Department of Human Genetics, Mount Sinai School of Medicine, New York, New York 
      10029, USA.
FAU - Rossetti, M V
AU  - Rossetti MV
FAU - Parera, V E
AU  - Parera VE
FAU - Astrin, K H
AU  - Astrin KH
FAU - Aizencang, G I
AU  - Aizencang GI
FAU - Glass, I A
AU  - Glass IA
FAU - Batlle, A M
AU  - Batlle AM
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  - United States
TA  - Am J Med Genet
JT  - American journal of medical genetics
JID - 7708900
RN  - 0 (DNA Primers)
RN  - EC 2.5.1.61 (Hydroxymethylbilane Synthase)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Argentina
MH  - Base Sequence
MH  - Child
MH  - DNA Mutational Analysis
MH  - DNA Primers/genetics
MH  - Escherichia coli/genetics
MH  - Female
MH  - Founder Effect
MH  - Genes, Dominant
MH  - Genetic Counseling
MH  - Haplotypes
MH  - Heterozygote
MH  - Humans
MH  - Hydroxymethylbilane Synthase/*genetics
MH  - Male
MH  - Middle Aged
MH  - Pedigree
MH  - *Point Mutation
MH  - Polymerase Chain Reaction/methods
MH  - Polymorphism, Genetic
MH  - Porphyria, Acute Intermittent/*enzymology/*genetics
EDAT- 1999/09/24 00:00
MHDA- 1999/09/24 00:01
CRDT- 1999/09/24 00:00
PHST- 1999/09/24 00:00 [pubmed]
PHST- 1999/09/24 00:01 [medline]
PHST- 1999/09/24 00:00 [entrez]
AID - 10.1002/(SICI)1096-8628(19991008)86:4<366::AID-AJMG11>3.0.CO;2-# [pii]
PST - ppublish
SO  - Am J Med Genet. 1999 Oct 8;86(4):366-75.