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Clinical and biochemical characterization of 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) deficiency that causes Leigh-like disease and ketoacidosis

View Article: PubMed Central - PubMed

ABSTRACT

3-Hydroxyisobutyryl-CoA hydrolase (HIBCH) deficiency is an autosomal recessive disorder characterized by episodes of ketoacidosis and a Leigh-like basal ganglia disease, without high concentrations of pyruvate and lactate in the cerebrospinal fluid. Only 4 cases of HIBCH deficiency have been reported. However, clinical–biochemical correlation in HIBCH deficiency by determining the detailed residual enzyme activities has not yet been elucidated. Here, we report a case of two Japanese siblings with HIBCH deficiency carrying a new homozygous missense mutation (c.287C > A, [p.A96D]) at the substrate-binding site. A transfection study using HIBCH expression vectors harboring wild type or 4 reported mutations, including the newly identified mutation (p.A96D, p.Y122C, p.G317E, and p.K74Lfs*13), revealed a correlation between residual HIBCH activities and the severity of the disease. All HIBCH mutants, except p.K74Lfs*13, showed residual enzyme activity and only the patient with p.K74Lfs*13 had congenital anomalies. p.G317E showed only low enzyme activity (~ 3%) of that of wild-type HIBCH. Although p.A96D had approximately 7 times higher enzyme activity than p.G317E, patients with p.A96D died during childhood. These findings are essential for clinical management, genetic counseling, and specific meal and concomitant drug considerations as part of the treatment for patients with HIBCH deficiency.

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Identification of the mutation in HIBCH. (A) Direct sequence analysis of DNA from patient II-2 revealed a C to A substitution at nucleotide position 287 in exon 4 of HIBCH, resulting in the substitution of alanine (GCC) with aspartic acid (GAC) at codon 96 (c.287C > A, [p.Ala96Asp]), as indicated by the arrow. (B) The pedigree of the family with HIBCH deficiency. Affected individuals are indicated by filled symbols, unaffected individuals by hollow symbols, and carrier individuals by half-filled symbols. PCR-RFLP analysis using MluI-digested PCR products from family members and 3 normal controls (C1, C2, and C3) were run on a 1.5% low-melting agarose gel. The size of the DNA markers is indicated on both sides. (C) Schematic representation of HIBCH. The positions of the mutations identified in the previously reported cases and the patients from this study are indicated by arrows. Predicted substrate-binding residues are indicated by arrowheads. A96 is a substrate-binding residue.
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f0010: Identification of the mutation in HIBCH. (A) Direct sequence analysis of DNA from patient II-2 revealed a C to A substitution at nucleotide position 287 in exon 4 of HIBCH, resulting in the substitution of alanine (GCC) with aspartic acid (GAC) at codon 96 (c.287C > A, [p.Ala96Asp]), as indicated by the arrow. (B) The pedigree of the family with HIBCH deficiency. Affected individuals are indicated by filled symbols, unaffected individuals by hollow symbols, and carrier individuals by half-filled symbols. PCR-RFLP analysis using MluI-digested PCR products from family members and 3 normal controls (C1, C2, and C3) were run on a 1.5% low-melting agarose gel. The size of the DNA markers is indicated on both sides. (C) Schematic representation of HIBCH. The positions of the mutations identified in the previously reported cases and the patients from this study are indicated by arrows. Predicted substrate-binding residues are indicated by arrowheads. A96 is a substrate-binding residue.

Mentions: Whole-exome analysis of genomic DNA from a family member revealed a novel missense mutation (c.287C > A, [p.A96D]) in exon 4 of HIBCH on chromosome 2q32.3 (Fig. 2A). A96 is one of the substrate-binding residues in HIBCH and is highly conserved in eukaryotes (e.g., Arabidopsis thaliana, Caenorhabditis elegans, and other higher eukaryotes whose sequence information is available in the NCBI reference protein database; Fig. 2C). The mutation is absent from the NCBI reference assembly SNP database and could not be located using the Human Genetic Variation Browser. The mutation has a maximum predicted pathogenicity score, as determined by Polyphen-2 [12]. Direct sequencing and PCR-RFLP analysis demonstrated that both patients were homozygous for the mutation and that their parents were heterozygous (Fig. 2B). We could not trace the relationship beyond the grandparents of the parents. However, ancestors of the grandparents of the parents lived in the same prefecture of Japan, raising the possibility that the patients and their parents in the present study have inherited the same mutation from a common ancestor.


Clinical and biochemical characterization of 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) deficiency that causes Leigh-like disease and ketoacidosis
Identification of the mutation in HIBCH. (A) Direct sequence analysis of DNA from patient II-2 revealed a C to A substitution at nucleotide position 287 in exon 4 of HIBCH, resulting in the substitution of alanine (GCC) with aspartic acid (GAC) at codon 96 (c.287C > A, [p.Ala96Asp]), as indicated by the arrow. (B) The pedigree of the family with HIBCH deficiency. Affected individuals are indicated by filled symbols, unaffected individuals by hollow symbols, and carrier individuals by half-filled symbols. PCR-RFLP analysis using MluI-digested PCR products from family members and 3 normal controls (C1, C2, and C3) were run on a 1.5% low-melting agarose gel. The size of the DNA markers is indicated on both sides. (C) Schematic representation of HIBCH. The positions of the mutations identified in the previously reported cases and the patients from this study are indicated by arrows. Predicted substrate-binding residues are indicated by arrowheads. A96 is a substrate-binding residue.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5121361&req=5

f0010: Identification of the mutation in HIBCH. (A) Direct sequence analysis of DNA from patient II-2 revealed a C to A substitution at nucleotide position 287 in exon 4 of HIBCH, resulting in the substitution of alanine (GCC) with aspartic acid (GAC) at codon 96 (c.287C > A, [p.Ala96Asp]), as indicated by the arrow. (B) The pedigree of the family with HIBCH deficiency. Affected individuals are indicated by filled symbols, unaffected individuals by hollow symbols, and carrier individuals by half-filled symbols. PCR-RFLP analysis using MluI-digested PCR products from family members and 3 normal controls (C1, C2, and C3) were run on a 1.5% low-melting agarose gel. The size of the DNA markers is indicated on both sides. (C) Schematic representation of HIBCH. The positions of the mutations identified in the previously reported cases and the patients from this study are indicated by arrows. Predicted substrate-binding residues are indicated by arrowheads. A96 is a substrate-binding residue.
Mentions: Whole-exome analysis of genomic DNA from a family member revealed a novel missense mutation (c.287C > A, [p.A96D]) in exon 4 of HIBCH on chromosome 2q32.3 (Fig. 2A). A96 is one of the substrate-binding residues in HIBCH and is highly conserved in eukaryotes (e.g., Arabidopsis thaliana, Caenorhabditis elegans, and other higher eukaryotes whose sequence information is available in the NCBI reference protein database; Fig. 2C). The mutation is absent from the NCBI reference assembly SNP database and could not be located using the Human Genetic Variation Browser. The mutation has a maximum predicted pathogenicity score, as determined by Polyphen-2 [12]. Direct sequencing and PCR-RFLP analysis demonstrated that both patients were homozygous for the mutation and that their parents were heterozygous (Fig. 2B). We could not trace the relationship beyond the grandparents of the parents. However, ancestors of the grandparents of the parents lived in the same prefecture of Japan, raising the possibility that the patients and their parents in the present study have inherited the same mutation from a common ancestor.

View Article: PubMed Central - PubMed

ABSTRACT

3-Hydroxyisobutyryl-CoA hydrolase (HIBCH) deficiency is an autosomal recessive disorder characterized by episodes of ketoacidosis and a Leigh-like basal ganglia disease, without high concentrations of pyruvate and lactate in the cerebrospinal fluid. Only 4 cases of HIBCH deficiency have been reported. However, clinical–biochemical correlation in HIBCH deficiency by determining the detailed residual enzyme activities has not yet been elucidated. Here, we report a case of two Japanese siblings with HIBCH deficiency carrying a new homozygous missense mutation (c.287C > A, [p.A96D]) at the substrate-binding site. A transfection study using HIBCH expression vectors harboring wild type or 4 reported mutations, including the newly identified mutation (p.A96D, p.Y122C, p.G317E, and p.K74Lfs*13), revealed a correlation between residual HIBCH activities and the severity of the disease. All HIBCH mutants, except p.K74Lfs*13, showed residual enzyme activity and only the patient with p.K74Lfs*13 had congenital anomalies. p.G317E showed only low enzyme activity (~ 3%) of that of wild-type HIBCH. Although p.A96D had approximately 7 times higher enzyme activity than p.G317E, patients with p.A96D died during childhood. These findings are essential for clinical management, genetic counseling, and specific meal and concomitant drug considerations as part of the treatment for patients with HIBCH deficiency.

No MeSH data available.


Related in: MedlinePlus