We performed homozygosity mapping in two recently reported pedigrees from Portugal and Mexico with an autosomal-recessive autoinflammatory syndrome characterized by joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy (JMP). This revealed only one homozygous region spanning 2.4 Mb (5818 SNPs) on chromosome 6p21 shared by all three affected individuals from both families. We directly sequenced genes involved in immune response located in this critical region, excluding the HLA complex genes. We found a homozygous missense mutation c.224C>T (p.Thr75Met) in the proteasome subunit, beta-type, 8 (PSMB8) gene in affected patients from both pedigrees. The mutation segregated in an autosomal-recessive fashion and was not detected in 275 unrelated ethnically matched healthy subjects. PSMB8 encodes a catalytic subunit of the 20S immunoproteasomes called β5i. Immunoproteasome-mediated proteolysis generates immunogenic epitopes presented by major histocompatibility complex (MHC) class I molecules. Threonine at position 75 is highly conserved and its substitution with methionine disrupts the tertiary structure of PSMB8. As compared to normal lymphoblasts, those from an affected patient showed significantly reduced chymotrypsin-like proteolytic activity mediated by immunoproteasomes. We conclude that mutations in PSMB8 cause JMP syndrome, most probably by affecting MHC class I antigen processing.

We conclude that these patients represent a novel autoinflammatory syndrome resulting in joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy. The molecular genetic basis of this disorder remains to be elucidated.

After 2 years there was a 50% decrease in the incidence of anencephaly and spina bifida cases with a significant reduction of infant mortality and disability. These results encourage us to propose the use of a single tablet of 5.0-mg of folic acid per week as an alternative to supplementation on a daily basis.

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Mouse embryos at day 9 of development were cultured for 24 to 42 h in 50% fetal calf serum and 50% Waymouth's medium containing 0.5 micrograms/ml insulin supplemented with various amounts of progesterone and estradiol-17-beta. Unmodified medium contained approximately 0.2% of the normal maternal blood levels for that stage of pregnancy. The addition of 1 X 10(-7)M progesterone to the medium brought the level near that of the normal maternal circulating amount and appeared to be beneficial for in vitro development. After 24 h of cultivation there was a statistically significant increase in somite number, the number of embryos developing posterior limb buds, and protein accumulation over the control embryos. The addition of small amounts of estradiol-17 beta (1 X 10(-10)M) increased the protein accumulation of the embryo over that of progesterone alone and seems to enhance the beneficial effects of progesterone addition.