Comparison of complementary and genomic DNA sequencing for the detection of mutations in the HMBS gene in British patients with acute intermittent porphyria: identification of 25 novel mutations
Sd. Whatley et al., Comparison of complementary and genomic DNA sequencing for the detection of mutations in the HMBS gene in British patients with acute intermittent porphyria: identification of 25 novel mutations, HUM GENET, 104(6), 1999, pp. 505-510
Acute intermittent porphyria (AIP) is a low-penetrant autosomal dominant di
sorder caused by mutations in the hydroxymethylbilane synthase (HMBS) gene.
Direct detection of mutations is becoming the method of choice for the acc
urate identification of asymptomatic affected individuals within AIP famili
es so that they can be advised to avoid drugs and other compounds that prov
oke the life-threatening acute neurovisceral crises that characterise the c
ondition. We describe a prospective comparison of direct automated sequenci
ng of cDNA (29 patients) or genomic DNA (28 patients) to identify HMBS muta
tions in 57 patients referred consecutively for mutational analysis; 39 dif
ferent mutations were identified in 54 patients. The sensitivity of the cDN
A and genomic DMA methods was 69% and 95%, respectively, indicating that an
alysis of genomic DNA provides a higher mutation detection rate. Thirty mut
ations were restricted to a single family; only one (R173W) occurred in mor
e than three families. Of the mutations (6 missense, 8 splice defects, 10 f
rameshifts, 1 nonsense), 25 have not been reported previously. One novel mu
tation (344+33G-->T) was located in a putative intron splice enhancer in in
tron 7. Our results define the extent of allelic heterogeneity and the type
s (41% missense; 59% truncating) and distribution (35% in exons 10, 12, 14)
of HMBS mutations, for AIP in the United Kingdom.