Sex hormone binding globulin deficiency due to a homozygous missense mutation.

CONTEXT: SHBG is known as the major sex steroid binding protein in plasma, and it regulates the bioavailability of both T and estradiol levels required for effects on target tissues. We identified a man with an undetectable SHBG concentration in combination with low total T. He presented with a 7-year history of muscle weakness, fatigue, and a low libido. OBJECTIVES: To determine the cause of the SHBG deficiency, we employed both genetic analysis of the SHBG gene and transgene SHBG expression. RESULTS: Genetic analysis identified a novel homozygous missense mutation that was predicted to be deleterious for protein function. Transgene expression showed that the mutation resulted in a block in SHBG secretion accompanied by increased expression of the endoplasmic reticulum molecular chaperone HSPA5. The mutation results in accumulation of the mutant SHBG within the cell and failure to secrete the mutant protein. Screening of family members identified one sister who was also deficient for SHBG. CONCLUSIONS: We have identified a family with a missense mutation within the SHBG gene, which results in a complete deficiency of plasma SHBG in the homozygous state. Although total T level was low in the male patient, it did not interfere with normal gonadal development and spermatogenesis, suggesting a limited role of SHBG in sexual maturation and male physiology.