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Identification and characterization of 40 novel hydroxymethylbilane synthase mutations that cause acute intermittent porphyria
Author(s) -
Chen Brenden,
SolisVilla Constanza,
Erwin Angelika L.,
Balwani Manisha,
Nazarenko Irina,
Phillips John D.,
Desnick Robert J.,
Yasuda Makiko
Publication year - 2019
Publication title -
journal of inherited metabolic disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 102
eISSN - 1573-2665
pISSN - 0141-8955
DOI - 10.1002/jimd.12040
Subject(s) - acute intermittent porphyria , missense mutation , exon , genetics , biology , microbiology and biotechnology , mutation , mutant , porphobilinogen , gene , porphyria , endocrinology
Acute intermittent porphyria (AIP), an autosomal dominant disorder due to the half‐normal activity of hydroxymethylbilane synthase (HMBS), is characterized by acute neurovisceral attacks that are precipitated by factors that induce heme biosynthesis. Molecular diagnosis is the most sensitive and specific diagnostic test for AIP, and importantly, it permits the identification of asymptomatic family members for genetic counseling and avoidance of precipitating factors. Here, we report the identification of 40 novel HMBS mutations, including 11 missense, four nonsense, 16 small insertions or deletions, eight consensus splice site mutations, and a complex insertion‐deletion mutation in unrelated individuals with AIP. Prokaryotic expression of the missense mutations demonstrated that all mutants had ≤5% of expressed wildtype activity, except for c.1039G>C (p.A347P), which had 51% residual HMBS activity but was markedly thermolabile. Of note, the mutation c.612G>T (p.Q204H) altered the last nucleotide of exon 10, which resulted in an alternative HMBS transcript with an in‐frame nine base‐pair deletion at the 3'‐terminus of exon 10 (encoding protein Q204HΔ3). When expressed, Q204HΔ3 and an in‐frame three base‐pair deletion (c.639_641delTGC) had no detectable HMBS activity. Western blot analyses and mapping of the missense mutations on the human HMBS crystal structure revealed that mutations near the active site or at the dimerization interface resulted in stably expressed proteins, while most that altered surface residues resulted in unstable proteins, presumably due to improper protein folding. These studies identified novel pathogenic HMBS mutations and expanded the molecular heterogeneity of AIP.