title: Mutations in HADHB, which encodes the β-subunit of mitochondrial trifunctional protein, cause infantile onset hypoparathyroidism and peripheral polyneuropathy.
abstract: Mitochondrial trifunctional protein (MTP) is a hetero-octamer composed of four α- and four β-subunits that catalyzes the final three steps of mitochondrial β-oxidation of long chain fatty acids. HADHA and HADHB encode the α-subunit and the β-subunit of MTP, respectively. To date, only two cases with MTP deficiency have been reported to be associated with hypoparathyroidism and peripheral polyneuropathy. Here, we report on two siblings with autosomal recessive infantile onset hypoparathyroidism, peripheral polyneuropathy, and rhabdomyolysis. Sequence analysis of HADHA and HADHB in both siblings shows that they were homozygous for a mutation in exon 14 of HADHB (c.1175C>T, [p.A392V]) and the parents were heterozygous for the mutation. Biochemical analysis revealed that the patients had MTP deficiency. Structural analysis indicated that the A392V mutation identified in this study and the N389D mutation previously reported to be associated with hypoparathyroidism are both located near the active site of MTP and affect the conformation of the β-subunit. Thus, the present patients are the second and third cases of MTP deficiency associated with missense HADHB mutation and infantile onset hypoparathyroidism. Since MTP deficiency is a treatable disease, MTP deficiency should be considered when patients have hypoparathyroidism as the initial presenting feature in infancy.
authors.affiliation: Department of Genetics, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Aichi, Japan; Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
authors.forename: Misako
authors.initials: M
authors.lastname: Naiki
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Ochi
authors.forename: Yusuke S
authors.initials: YS
authors.lastname: Kato
authors.forename: Jamiyan
authors.initials: J
authors.lastname: Purevsuren
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Yamada
authors.forename: Reiko
authors.initials: R
authors.lastname: Kimura
authors.forename: Daisuke
authors.initials: D
authors.lastname: Fukushi
authors.forename: Shinya
authors.initials: S
authors.lastname: Hara
authors.forename: Yasukazu
authors.initials: Y
authors.lastname: Yamada
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Kumagai
authors.forename: Seiji
authors.initials: S
authors.lastname: Yamaguchi
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Wakamatsu
mesh_terms: D000293:Adolescent; D002675:Child, Preschool; D003241:Consanguinity; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D007011:Hypoparathyroidism / Q000151:congenital* / Q000175:diagnosis / Q000235:genetics; D007223:Infant; D008297:Male; D063993:Mitochondrial Trifunctional Protein, beta Subunit / Q000737:chemistry / Q000235:genetics*; D008958:Models, Molecular; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D011115:Polyneuropathies / Q000175:diagnosis* / Q000235:genetics*; D011487:Protein Conformation; D035781:Siblings; D014429:Twins, Dizygotic
chemical_list: C576206:HADHB protein, human; D063993:Mitochondrial Trifunctional Protein, beta Subunit
keywords: HADHB; LCKT; MTP deficiency; hypoparathyroidism; peripheral polyneuropathy