Familial pulmonary Mycobacterium avium complex disease

We report two Japanese families affected by pulmonary Mycobacterium avium c omplex (MAC) disease, involving an older brother and younger sister in one family and two brothers in the second family. We investigated whether defec ts in the natural resistance-associated macrophage protein gene (NRAMP1) un derlay susceptibility to MAC in these cases. All of the patients had comput ed tomographic findings of peripheral nodules and bronchiectasis. Pulse-fie ld gel electrophoresis patterns of mycobacterial genomic DNA restriction fr agments revealed that none of the MAC strains isolated from the patients wa s epidemiologically related to any of the others. Direct sequencing of the complementary DNA of the patients' NRAMP1 revealed a nonconservative missen se mutation at codon 419 in one patient, which was heterozygous and was not seen in his affected sibling. No variations similar to those found in mice that show susceptibility to MAC were found. The results suggest an underly ing genetic defect in host defense rather than exposure to an unusually vir ulent strain of MAC as the pathogenetic factor in MAC disease; however, alt erations in the coding region of NRAMP1 do not appear to explain the suscep tibility to MAC.