MOLECULAR ANALYSIS OF HOLOCARBOXYLASE SYNTHETASE DEFICIENCY - A MISSENSE MUTATION AND A SINGLE-BASE DELETION ARE PREDOMINANT IN JAPANESE PATIENTS

Holocarboxylase synthetase (HCS) deficiency is an inherited disease of biotin metabolism characterized by a unique pattern of organic acidur ia, metabolic acidosis, and skin lesions. By analysis of five patients in four unrelated families, two mutations were identified: a transiti on from T to C which causes an amino-acid substitution of proline for leucine at position 237 (L237P) and a single deletion of guanine (delG 1067) followed by premature termination. One patient was homozygous fo r the L237P mutation, three patients in two families were compound het erozygotes of the missense and deletion alleles, and the other patient was heterozygous for the L237P mutation. Inheritance was successfully demonstrated in all of the patients' families by a modified PCR follo wed by restriction enzyme digestion. The two mutations accounted for s even of eight mutant alleles, while neither mutation was detected in 1 08 normal healthy Japanese children (216 alleles). Transient expressio n in cultured fibroblasts from a patient showed that the L237P mutatio n was responsible for decreased HCS activity. These results suggest th at the L237P and delG1067 mutations are frequent disease-causing mutat ions in Japanese patients with HCS deficiency. This PCR-based techniqu e may therefore be useful for detecting mutations among Japanese patie nts.