Human Genetics

, Volume 116, Issue 5, pp 340–346 | Cite as

Molecular characterization of histidinemia: identification of four missense mutations in the histidase gene

  • Yoko Kawai
  • Akihiko Moriyama
  • Kiyofumi Asai
  • Carrie M. Coleman-Campbell
  • Satoshi Sumi
  • Hideko Morishita
  • Mariko Suchi
Original Investigation


Histidinemia (MIM235800) is characterized by elevated histidine in body fluids and decreased urocanic acid in blood and skin and results from histidase (histidine ammonia lyase, EC deficiency. It is the most frequent inborn metabolic error in Japan. Although the original description included mental retardation and speech impairment, neonatal screening programs have identified the majority of histidinemic patients with normal intelligence. Molecular characteristics of histidase in histidinemia have not been determined, and cytogenetically visible deletions of 12q22-24.1 in which histidase gene resides have not been identified in histidinemic patients. In order to investigate whether individuals with this disorder have small deletions, additions, or point mutations in the histidase gene, we screened genomic DNA isolated from 50 histidinemic individuals who were discovered by the neonatal screening program. The methods employed included polymerase chain reaction (PCR) amplification of exons 1–21 of the histidase gene, followed by mutation detection enhancement gel electrophoresis and sequencing of the PCR products displaying heteroduplex bands. Four missense mutations (R322P, P259L, R206T, and R208L), two exonic polymorphisms (T141T c.423A→T and P259P c.777A→G), and two intronic polymorphisms (IVS6−5T→C and IVS9+25A→G) were identified. The frequencies of each polymorphism estimated either by dot blot allele-specific oligonucleotide hybridization, restriction enzyme digestion, or direct sequencing of the PCR products amplified from 50 unrelated normal individuals were 0.28, 0.30, 0.40, and less than 0.01, respectively. Mutation analysis of one family demonstrated that the patient inherited R322P from the mother and P259L from the father. This report describes the first mutations occurring in the coding region of the histidase structural gene in patients with histidinemia.


Polymerase Chain Reaction Product Base Change Newborn Screening Program Urocanic Acid Neonatal Screening Program 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



We thank the late Dr. Taiji Kato for graciously providing access to his laboratory facilities in the Department of Molecular Neurobiology, Drs. Yoshiro Wada and Hisako Saito for their seminal work and continuous encouragement, Dr. Haruo Mizuno for the preparation of genomic DNA from normal individuals, and Manami Yamamoto for her technical assistance. We are also grateful to physicians in the Department of Pediatrics, Neonatology and Congenital Disorders, Nagoya City University for the care of the patients and to laboratory staff members of the General Clinical Research Center, The Children’s Hospital of Philadelphia for their technical support. This study was supported in part by a Research Grant from the Ministry of Health, Labor, and Welfare of Japan and NIH/NRCC grant M01-RR00240.


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Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Yoko Kawai
    • 1
  • Akihiko Moriyama
    • 2
  • Kiyofumi Asai
    • 3
  • Carrie M. Coleman-Campbell
    • 5
  • Satoshi Sumi
    • 4
  • Hideko Morishita
    • 4
  • Mariko Suchi
    • 4
    • 6
    • 6
  1. 1.Pediatric NursingNagoya City University School of NursingNagoyaJapan
  2. 2.Graduate School of Natural SciencesNagoya City UniversityNagoyaJapan
  3. 3.Department of Molecular Neurobiology, Graduate School of Medical SciencesNagoya City UniversityNagoyaJapan
  4. 4.Department of Pediatrics, Neonatology and Congenital Disorders, Graduate School of Medical SciencesNagoya City UniversityNagoyaJapan
  5. 5.The General Clinical Research CenterThe Children’s Hospital of PhiladelphiaPhiladelphiaUSA
  6. 6.Department of Pathology and Laboratory Medicine, The Children’s Hospital of PhiladelphiaUniversity of Pennsylvania School of MedicinePhiladelphiaUSA

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