TY - JOUR
T1 - δ-Aminolevulinate dehydratase (ALAD) porphyria
T2 - The first case in North America with two novel ALAD mutations
AU - Akagi, Reiko
AU - Kato, Noriko
AU - Inoue, Rikako
AU - Anderson, Karl E.
AU - Jaffe, Eileen K.
AU - Sassa, Shigeru
N1 - Funding Information:
We are grateful to Ms. Luba Garbaczewski for her skilled technical assistance, and for Dr. Jon Cooper for his helpful discussion. This study was supported in part by a Grant-in Aid for Scientific Research (15590252) from the Ministry of Education, Science, and Culture of Japan (R. Akagi) and a grant from The Okayama Medical Foundation (R. Akagi), USPHS DK32890 (S. Sassa), American Porphyria Foundation (K.E.Anderson and S. Sassa), the USPHS ES03654 (E.K. Jaffe) and the Commonwealth of Pennsylvania (E.K. Jaffe), and NIH/NCRR Grant MO1-RR-0073 to the General Clinical Research Center at the University of Texas Medical Branch.
PY - 2006/4
Y1 - 2006/4
N2 - The molecular basis of the enzymatic defect responsible for δ-aminolevulinate dehydratase (ALAD) porphyria (ADP) was investigated in a 14-year-old male who presented clinical and laboratory findings typical of ADP. Nucleotide sequence analysis of ALAD cDNAs from the proband revealed two novel mutations, a 265G to A base transition (C1) and a 394C to T base transition (C2), resulting in amino acid substitutions, Glu89Lys and Cys132Arg, respectively. Both mutations were present within exon 5 of the ALAD gene, and appeared to influence the binding of zinc to the enzyme which is essential for enzyme activity. It was found that the C1 mutation was inherited from his father, while the C2 mutation was from his mother. Expression of these mutant ALAD cDNAs in Chinese hamster ovary cells produced normal ALAD mRNA levels, but markedly decreased ALAD protein and enzyme activity. These results suggest that the combination of the two aberrant ALADs with little enzyme activity accounts for the markedly decreased ALAD activity observed in the proband. This case represents the molecular analysis of the ALAD gene defects in the first case of ADP identified in North America, who is a compound heterozygote for two novel ALAD gene defects.
AB - The molecular basis of the enzymatic defect responsible for δ-aminolevulinate dehydratase (ALAD) porphyria (ADP) was investigated in a 14-year-old male who presented clinical and laboratory findings typical of ADP. Nucleotide sequence analysis of ALAD cDNAs from the proband revealed two novel mutations, a 265G to A base transition (C1) and a 394C to T base transition (C2), resulting in amino acid substitutions, Glu89Lys and Cys132Arg, respectively. Both mutations were present within exon 5 of the ALAD gene, and appeared to influence the binding of zinc to the enzyme which is essential for enzyme activity. It was found that the C1 mutation was inherited from his father, while the C2 mutation was from his mother. Expression of these mutant ALAD cDNAs in Chinese hamster ovary cells produced normal ALAD mRNA levels, but markedly decreased ALAD protein and enzyme activity. These results suggest that the combination of the two aberrant ALADs with little enzyme activity accounts for the markedly decreased ALAD activity observed in the proband. This case represents the molecular analysis of the ALAD gene defects in the first case of ADP identified in North America, who is a compound heterozygote for two novel ALAD gene defects.
KW - Compound heterozygote
KW - Doss porphyria
KW - Hepatic porphyria
KW - Point mutation
KW - δ-Aminolevulinate dehydratase
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U2 - 10.1016/j.ymgme.2005.10.011
DO - 10.1016/j.ymgme.2005.10.011
M3 - Article
C2 - 16343966
AN - SCOPUS:33645116987
SN - 1096-7192
VL - 87
SP - 329
EP - 336
JO - Molecular Genetics and Metabolism
JF - Molecular Genetics and Metabolism
IS - 4
ER -