Session: PP30-GnRH & Gonadotrope Biology & Signaling
Poster Board MON-0602
Methods: We screened 295 CHH patients for mutations in KLB and FGF21. The functionality of identified mutations were evaluated in vitro using cell-based reporter gene assays and expression assays, as well as in vivo using rescue experiments in C.elegans deficient of both worm KLB homologues. Klb deficient mice (Klb-/-) were evaluated for reproductive and metabolic phenotypes.
Results: No mutations were identified in FGF21. We identified 9 heterozygous KLB mutations among 13/295 unrelated CHH patients (4%, 9 males and 4 females). Five patients harbor an identical KLB deletion (p.Phe777del) while the other mutations are missense. All mutations have a MAF<1% in EVS and 1000 genome database and are LOF in vitro and/or in vivo. Additional gene defects in CHH-associated genes were identified in 6/13 patients; these including 3 heterozygous FGFR1 mutations, consistent with an oligogenic model of inheritance. Notably, 10/13 subjects also exhibited metabolic defects, such as obesity, impaired fasting glucose, and/or severe dyslipidemia. Klb-/- mice are smaller in size than wild-type littermates. Female Klb-/- exhibit delayed sexual maturation and irregular estrous cycles, with reduced time spent in estrous. Further reproductive and metabolic phenotyping of the Klb-/-mice is underway.
Conclusion: Loss-of-function KLB mutations underlie congenital GnRH deficiency. The delayed puberty phenotype of Klb-/- mice supports a role for KLB in reproduction. These findings highlight FGF21 as a probable important link between metabolism and reproduction.
Nothing to Disclose: ES, CX, HM, TK, NP, AD, GS, RQ, WFC Jr., MH, FP, YS, MM, NP
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