HMBS Mutations in Chinese Patients with Acute Intermittent Porphyria

Abstract

SummaryAcute intermittent porphyria (AIP), an autosomal dominant disorder, is caused by partial deficiency of hydroxymethylbilane synthase (HMBS) affecting heme biosynthesis. Patients with AIP are characterized by recurrent abdominal pain, port-wine urine, and motor paresis. The disease can be provoked by changes in hormone levels, drugs and fasting. Molecular analysis for twenty-four unrelated Chinese AIP patients from Taiwan identified twenty-five HMBS mutations. There were 10 missense (40%), four nonsense (16%), five frame-shift (20%) and six splice site (24%) mutations. More than a half (15/25, 60%) of these mutations are predicted to produce a truncated protein. Four (c.33 + 5C>A, Arg26Cys, Arg26His, Arg325X) occurred more than once among the 24 families and one individual carried two mutations in the same allele, a missense (Gly221Asp) and a splice site mutation (c.652-1G>A). Of the 25 mutations, eleven were novel (Arg149Pro, Gly218Arg, Asn322X, Gly221Asp, Pro313X, c.88-4_-16delAAGTCTCTACCCG, c.1008_1019delCAGCCTGGCCAA, c.113delT, c.88-4_-16delAAGTCTCTACCCGinsCA, c.160delA, c.902_909delTCCCTGCC). No correlation between genetic defect and phenotype (both clinical and biochemical) was observed in this study.

Secret Underlying Unexplained Abdominal Pain, Neurological Symptoms and Intermittent Hypertension: Acute Intermittent Porphyria

“…Due to the diagnosis of type 1 diabetes, dextrose and insulin were administered at same time. Yang et al have studied the types of HMBS mutations in Chinese patients with AIP and identified twenty-five HMBS mutations [11]. We found HMBS IVS13-2 A>G heterozygous mutation in our patient.…”

Diagnostic Strategies for Autosomal Dominant Acute Porphyrias: Retrospective Analysis of 467 Unrelated Patients Referred for Mutational Analysis of the HMBS, CPOX, or PPOX Gene

“…Identification of disease-specific mutations in the corresponding genes (HMBS, 4 CPOX, and PPOX, respectively) is important for detection and counseling of asymptomatic relatives in families with acute porphyria (1 ). Of the at least 510 mutations that have been identified in these genes (www.hgmd.cf.ac.uk) (3)(4)(5)(6)(7)(8), most are restricted to one or a few families (9,10 ).…”

Novel A219P Mutation of Hydroxymethylbilane Synthase Identified in a Chinese Woman with Acute Intermittent Porphyria and Syndrome of Inappropriate Antidiuretic Hormone

“…Therefore, both patients were diagnosed with SIADH. SIADH was noted in approximately 20% of patients with symptomatic AIP in a study of 25 Asians (Yang et al, 2008). This disease can be life-threatening.…”

“…Any mutation located in the binding region may disrupt the interaction with the DPM cofactor or disrupt substrate docking during catalysis. Previously reported mutations, such as Q217L, G218R, A219D, G221D, and V222M, caused enzyme abnormalities (Mustajoki et al, 1998;Whatley et al, 1999;Schneider-Yin et al, 2000;Yang et al, 2008). Without additional protein expression measurements, the enzyme activity was assayed from all individuals.…”

“…Ala219 appears to be a highly evolutionarily conserved amino acid that marks the active site cleft of human HMBS and is in close proximity to the dipyrromethane (DPM) cofactor as shown in the image of the HMBS structure (Gill et al, 2009). Ala219 and the nearby residues, such as Gln217 and Gly218, were reported to trigger AIP (Whatley et al, 1999;Schneider-Yin et al, 2000;Yang et al, 2008). The loss of enzyme activity is attributed to the location of these amino acids at the active site where these residues typically interact with DPM.…”