Mutations underlying 3-hydroxy-3-methylglutaryl CoA lyase deficiency in the Saudi population

Abstract

Background: 3-hydroxy-3-methylglutaric aciduria (3HMG, McKusick: 246450) is an autosomal recessive branched chain organic aciduria caused by deficiency of the enzyme 3-Hydroxy-3-Methylglutaryl CoA lyase (HL, HMGCL, EC 4.1.3.4). HL is encoded by HMGCL gene and many mutations have been reported. 3HMG is commonly observed in Saudi Arabia.

Methods: We utilized Whole Genome Amplification (WGA), PCR and direct sequencing to identify mutations underlying 3HMG in the Saudi population. Two patients from two unrelated families and thirty-four 3HMG positive dried blood spots (DBS) were included.

Results: We detected the common missense mutation R41Q in 89% of the tested alleles (64 alleles). 2 alleles carried the frame shift mutation F305fs (-2) and the last two alleles had a novel splice site donor IVS6+1G>A mutation which was confirmed by its absence in more than 100 chromosomes from the normal population. All mutations were present in a homozygous state, reflecting extensive consanguinity. The high frequency of R41Q is consistent with a founder effect. Together the three mutations described account for >94% of the pathogenic mutations underlying 3HMG in Saudi Arabia.

Conclusion: Our study provides the most extensive genotype analysis on 3HMG patients from Saudi Arabia. Our findings have direct implications on rapid molecular diagnosis, prenatal and pre-implantation diagnosis and population based prevention programs directed towards 3HMG.

Figure 1

Sequence analysis of PCR-amplified fragments of the HMGCL gene of patients and controls. A: The arrow indicates a heterozygous R41Q (122 G>A) mutation in a carrier of 3HMG; B: The position of the arrow indicates a homozygous F305fs (-2) (-TT) mutation in an affected 3HMG patient and C: The arrow indicates a homozygous IVS6+1G>A mutation in an affected 3HMG patient.