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Loss-of-Function Mutations in the Genes Encoding Prokineticin-2 or Prokineticin Receptor-2 Cause Autosomal Recessive Kallmann Syndrome

Developmental Endocrinology Unit (A.P.A., E.B.T., E.M.F.C., B.B.M., A.C.L.), Laboratory of Hormone and Molecular Genetic Laboratory of Medical Investigation-42, Clinical Hospital, Medical School, Sao Paulo University, 05403-900 Sao Paulo, Brazil; Department of Internal Medicine (M.d.C., B.V.), Clinical Hospital, Medical School of Ribeirao Preto University of Sao Paulo, 14049-900 Ribeirao Preto, Brazil; and Department of Internal Medicine (M.T.M.B., H.M.G.), Clinical Hospital, State University of Campinas, Campinas, 13083-970 Sao Paulo, Brazil

Address all correspondence and requests for reprints to: Ana Claudia Latronico or Ana Paula Abreu, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, Disciplina de Endocrinologia e Metabologia, Avenue Dr. Eneas de Carvalho Aguiar, 155, 2 degree andar Bloco 6, 05403-900 Sao Paulo, SP, Brasil. E-mail: anacl{at}usp.br or apaulabreu{at}yahoo.com.br.

Context: Physiological activation of the prokineticin pathway has a critical role in olfactory bulb morphogenesis and GnRH secretion in mice.

Objective: To investigate PROK2 and PROKR2 mutations in patients with hypogonadotropic hypogonadism (HH) associated or not with olfactory abnormalities.

Design: We studied 107 Brazilian patients with HH (63 with Kallmann syndrome and 44 with normosmic HH) and 100 control individuals. The coding regions of PROK2 and PROKR2 were amplified by PCR followed by direct automatic sequencing.

Results: In PROK2, two known frameshift mutations were identified. Two brothers with Kallmann syndrome harbored the homozygous p.G100fsX121 mutation, whereas one male with normosmic HH harbored the heterozygous p.I55fsX56 mutation. In PROKR2, four distinct mutations (p.R80C, p.Y140X, p.L173R, and p.R268C) were identified in five patients with Kallmann syndrome and in one patient with normosmic HH. These mutations were not found in the control group. The p.R80C, p.L173R, and p.R268C missense mutations were identified in the heterozygous state in the HH patients and in their asymptomatic first-degree relatives. In addition, no mutations of FGFR1, KAL1, GnRHR, KiSS-1, or GPR54 were identified in these patients. Notably, the new nonsense mutation (p.Y140X) was identified in the homozygous state in an anosmic boy with micropenis, bilateral cryptorchidism, and high-arched palate. His asymptomatic parents were heterozygous for this severe defect.

Conclusion: We expanded the repertoire of PROK2 and PROKR2 mutations in patients with HH. In addition, we show that PROKR2 haploinsufficiency is not sufficient to cause Kallmann syndrome or normosmic HH, whereas homozygous loss-of-function mutations either in PROKR2 or PROK2 are sufficient to cause disease phenotype, in accordance with the Prokr2 and Prok2 knockout mouse models.