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In vitro analysis showed that the Y59D mutant had significant impairment of cAMP generation, and both mutants caused a shift in the dose-response curve to the right when compared to wild type. Immunocytochemistry showed normal trafficking of MC2R when transfected with both mutant MRAPs, indicating a probable signaling defect. Conclusion Methods and Patients:The entire coding region of the FGF8 gene was amplified and sequenced in two well-phenotyped IHH probands and their relatives. Results: Two unique heterozygous nonsense mutations in FGF8 (p.R127X and p.R129X) were identified in two unrelated IHH probands, which were absent in 150 control individuals. These two mutations, mapped to the core domain of FGF8, impact all four human FGF8 isoforms, and lead to the deletion of a large portion of the protein, generating nonfunctional FGF8 ligands. The p.R127X mutation was identified in an 18-yr-old Kallmann syndrome female. Her four affected siblings with normosmic IHH or delayed puberty also carried the p.R127X mutation. Additional developmental anomalies, including cleft lip and palate and neurosensorial deafness, were also present in this family. The p.R129X mutation was identified in a 30-yr-old man with familial normosmic IHH and severe GnRH deficiency. Conclusions:We identified the first nonsense mutations in the FGF8 gene in familial IHH with variable degrees of GnRH deficiency and olfactory phenotypes, confirming that loss-of-function mutations in FGF8 cause human GnRH deficiency. Serum 25-Hydroxyvitamin D and Depressive Symptoms in Older Women and MenYuri Milaneschi, Michelle Shardell, Anna Maria Corsi, Rosamaria Vazzana, Stefania Bandinelli, Jack M. Guralnik, and Luigi Ferrucci Design and Setting:We conducted a population-based cohort study (InCHIANTI Study) in Tuscany, Italy. Participants: A total of 531 women and 423 men aged 65 yr and older participated. Main Outcome Measure: Serum 25(OH)D was measured at baseline. Depressive symptoms were assessed at baseline and at 3-and 6-yr follow-ups using the Center for Epidemiological Studies-Depression Scale (CES-D). Depressed mood was defined as CES-D of 16 or higher. Analyses were stratified by sex and adjusted for relevant biomarkers and variables related to sociodemographics, somatic health, and functional status. Results: Women with 25(OH)D less than 50 nmol/liter compared with those with higher levels experienced increases in CES-D scores of 2.1 (P ϭ 0.02) and 2.2 (P ϭ 0.04) points higher at, respectively, 3-and 6-yr follow-up. Women with low vitamin D (Vit-D) had also significantly higher risk of developing depressive mood over the follow-up (hazard ratio ϭ 2.0; 95% confidence interval ϭ 1.2-3.2; P ϭ 0.005). In parallel models, men with 25(OH)D less than 50 nmol/liter compared with those with higher levels expeEndocrine Reviews, June 2010, 31(3):396 -406 edrv.endojournals.org 397 Downloaded from https://academic.oup.

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