Loss-of-function mutations in the genes encoding prokineticin-2 or prokineticin receptor-2 cause autosomal recessive Kallmann syndrome

Autor(es)

Abreu, Ana Paula ^[1] ; Trarbach, Ericka Barbosa ^[1] ; de Castro, Margaret ^[2] ; Frade Costa, Elaine Maria ^[1] ; Versiani, Beatriz ^[2] ; Matias Baptista, Maria Tereza ^[3] ; Garmes, Heraldo Mendes ^[3] ; Mendonca, Berenice Bilharinho ^[1] ; Latronico, Ana Claudia ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Hosp Clin, Disciplina Endocrinol & Metab, Fac Med, Dev Endocrinol Unit, Sch Med, Lab Hormone, BR-05403900 Sao Paulo - Brazil

^[2] Univ Sao Paulo, Med Sch Ribeirao Preto, Clin Hosp, Dept Internal Med, BR-14049900 Ribeirao Preto - Brazil

^[3] Univ Estadual Campinas, Clin Hosp, Dept Internal Med, BR-13083970 Campinas, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM; v. 93, n. 10, p. 4113-4118, OCT 2008.
• Citações Web of Science: 69

Resumo

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, nomutations 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. (AU)

• Processo FAPESP: 07/50938-4 - Determinação da base molecular do hipogonadotrófico isolado congênito
• Beneficiário: Ericka Barbosa Trarbach
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 06/56753-3 - Pesquisa de mutações no gene do receptor da proquineticina 2 em pacientes com Síndrome de Kallmann
• Beneficiário: Ana Paula de Abreu e Silva
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto
• Processo FAPESP: 05/04726-0 - Caracterização molecular das doenças endócrinas congênitas que afetam o crescimento e o desenvolvimento
• Beneficiário: Ana Claudia Latronico Xavier
• Modalidade de apoio: Auxílio à Pesquisa - Temático