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An arginine to glutamine substitution in the triple helix of proalpha2(I)collagen (R618Q) was first reported in a patient with a variant of Marfan syndrome and later identified in conjunction with a second mutation in a patient with osteogenesis imperfecta (OI). The presence of the R618Q proalpha2(I)collagen allele in unaffected or mildly affected family members suggests that the R618Q allele is either a non-affecting polymorphism or a potential genetic modifier. Conservation of arginine618 across species and fibrillar collagen types suggests it is functionally significant. To investigate the functional significance of the R618Q proalpha2(I)collagen allele, we isolated type I collagen from cultured dermal fibroblasts of control and two unrelated individuals heterozygous for the R618Q proalpha2(I)collagen allele and evaluated helical stability and fibrillar assembly. Type I collagen thermal stability analyzed by protease susceptibility and CD spectroscopy demonstrated no statistical difference between control and R618Q containing collagen molecules. In vitro fibril assembly analyses demonstrated that R618Q containing collagen exhibits rapid fibrillar growth with minimal fibril nucleation phase. Further, electron microscopy demonstrated that the diameter of assembled R618Q containing collagen fibrils was approximately 20% of control collagen fibrils. These findings suggest the R618Q variant does not impact triple helical stability but has a role in collagen fibril assembly, supporting the hypothesis that the R618Q proalpha2(I)collagen variant is a modifier of connective tissue structure/function and is potentially involved in disease pathogenesis.

The effects of dietary histidine and arginine on fasting and 1 and 2 hour postprandial plasma free amino acid and urea concentrations were studied in six young men. For 1 week each, they were fed six different diets containing 6.3 g of nitrogen daily. Each diet contained eight indispensable amino acids, cystine and tyrosine proportioned as in casein and a different mixture of dispensable nitrogen: A) six dispensable amino acids plus argine (diet 1) or plus histidine and arginine (diet 2) in the casein pattern, or B) an isonitrogenous amount of glycine and diammonium citrate alone (diet 3), with histidine (diet 4), with arginine (diet 5) or with histidine and arginine (diet 6). The fasting plasma concentrations of the seven indispensable amino acids assayed and their similar postprandial patterns were unaffected by the dietary treatments. Both fasting and postprandial plasma histidine concentrations were significantly lower when the histidine-low diets were fed than when the histidine-supplemented diets were fed. Histidine supplementation promoted a reduction in fasting plasma urea nitrogens. Proline concentrations were lowered significantly when proline was removed from the dietary amino acid mixtures, but plasma arginine concentrations were unaffected by arginine removal. Plasma histidine was maintained at lower concentrations in dietary histidine deficiency than when histidine was added to the low nitrogen diets.

Effects of dietary histidine and arginine on nitrogen retention were compared in six young men consuming for 1 week, each of six semipurified diets containing eight indispensable amino acids proportioned as in casein and 6.3 g nitrogen daily. Nonspecific nitrogen was either A) a mixture of six dispensable amino acids and arginine (diet 1) or arginine and histidine (diet 2) in casein proportions, or B) an isonitrogenous mixture of glycine and diammonium citrate alone (diet 3), with histidine (diet 4), arginine (diet 5), or histidine and arginine (diet 6). Nitrogen retention was significantly greater when the nonspecific nitrogen source was dispensable amino acids, arginine and histidine (diet 2) than when it was glycine and diammonium citrate (diet 3). mean balances were positive only when diets contained histidine (diets 2, 4, and 6). Histidine with arginine (diets 2 and 6) significantly improved nitrogen retention compared to arginine alone, but the balance, although positive, was not significantly improved when histidine was fed without arginine (diet 4). Urinary urea nitrogen confirmed these data. Indicators of erythrocyte status, plasma enzyme activities and proteins, and creatinine clearance were unaffected by diet. In summary, histidine supplementation of the low nitrogen diet improved total nitrogen utilization when arginine was present in the diet.