KLB, encoding β‐Klotho, is mutated in patients with congenital hypogonadotropic hypogonadism

Cheng Xu, Andrea Messina, Emmanuel Somm, Hichem Miraoui, Tarja Kinnunen, James Acierno, Nicolas J Niederländer, Justine Bouilly, Andrew A Dwyer, Yisrael Sidis, Daniele Cassatella, Gerasimos P Sykiotis, Richard Quinton, Christian De Geyter, Mirjam Dirlewanger, Valérie Schwitzgebel, Trevor R Cole, Andrew A Toogood, Jeremy Mw Kirk, Lacey Plummer & 6 others Urs Albrecht, William F Crowley, Moosa Mohammadi, Manuel Tena‐sempere, Vincent Prevot, Nelly Pitteloud

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic form of isolated gonadotropin‐releasing hormone (GnRH) deficiency caused by mutations in > 30 genes. Fibroblast growth factor receptor 1 (FGFR1) is the most frequently mutated gene in CHH and is implicated in GnRH neuron development and maintenance. We note that a CHH FGFR1 mutation (p.L342S) decreases signaling of the metabolic regulator FGF21 by impairing the association of FGFR1 with β‐Klotho (KLB), the obligate co‐receptor for FGF21. We thus hypothesized that the metabolic FGF21/KLB/FGFR1 pathway is involved in CHH. Genetic screening of 334 CHH patients identified seven heterozygous loss‐of‐function KLB mutations in 13 patients (4%). Most patients with KLB mutations (9/13) exhibited metabolic defects. In mice, lack of Klb led to delayed puberty, altered estrous cyclicity, and subfertility due to a hypothalamic defect associated with inability of GnRH neurons to release GnRH in response to FGF21. Peripheral FGF21 administration could indeed reach GnRH neurons through circumventricular organs in the hypothalamus. We conclude that FGF21/KLB/FGFR1 signaling plays an essential role in GnRH biology, potentially linking metabolism with reproduction.
LanguageEnglish
Pages1379-1397
Number of pages9
JournalEMBO Molecular Medicine
Volume9
Issue number10
Early online date28 Jul 2017
DOIs
Publication statusPublished - 1 Aug 2017

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Receptor, Fibroblast Growth Factor, Type 1
Hypogonadism
Gonadotropin-Releasing Hormone
Mutation
Neurons
Delayed Puberty
Genetic Testing
Periodicity
Infertility
Genes
Hypothalamus
Reproduction
fibroblast growth factor 21
Maintenance

Cite this

Xu, Cheng ; Messina, Andrea ; Somm, Emmanuel ; Miraoui, Hichem ; Kinnunen, Tarja ; Acierno, James ; Niederländer, Nicolas J ; Bouilly, Justine ; Dwyer, Andrew A ; Sidis, Yisrael ; Cassatella, Daniele ; Sykiotis, Gerasimos P ; Quinton, Richard ; De Geyter, Christian ; Dirlewanger, Mirjam ; Schwitzgebel, Valérie ; Cole, Trevor R ; Toogood, Andrew A ; Kirk, Jeremy Mw ; Plummer, Lacey ; Albrecht, Urs ; Crowley, William F ; Mohammadi, Moosa ; Tena‐sempere, Manuel ; Prevot, Vincent ; Pitteloud, Nelly. / KLB, encoding β‐Klotho, is mutated in patients with congenital hypogonadotropic hypogonadism. In: EMBO Molecular Medicine. 2017 ; Vol. 9, No. 10. pp. 1379-1397.
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title = "KLB, encoding β‐Klotho, is mutated in patients with congenital hypogonadotropic hypogonadism",
abstract = "Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic form of isolated gonadotropin‐releasing hormone (GnRH) deficiency caused by mutations in > 30 genes. Fibroblast growth factor receptor 1 (FGFR1) is the most frequently mutated gene in CHH and is implicated in GnRH neuron development and maintenance. We note that a CHH FGFR1 mutation (p.L342S) decreases signaling of the metabolic regulator FGF21 by impairing the association of FGFR1 with β‐Klotho (KLB), the obligate co‐receptor for FGF21. We thus hypothesized that the metabolic FGF21/KLB/FGFR1 pathway is involved in CHH. Genetic screening of 334 CHH patients identified seven heterozygous loss‐of‐function KLB mutations in 13 patients (4{\%}). Most patients with KLB mutations (9/13) exhibited metabolic defects. In mice, lack of Klb led to delayed puberty, altered estrous cyclicity, and subfertility due to a hypothalamic defect associated with inability of GnRH neurons to release GnRH in response to FGF21. Peripheral FGF21 administration could indeed reach GnRH neurons through circumventricular organs in the hypothalamus. We conclude that FGF21/KLB/FGFR1 signaling plays an essential role in GnRH biology, potentially linking metabolism with reproduction.",
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author = "Cheng Xu and Andrea Messina and Emmanuel Somm and Hichem Miraoui and Tarja Kinnunen and James Acierno and Niederl{\"a}nder, {Nicolas J} and Justine Bouilly and Dwyer, {Andrew A} and Yisrael Sidis and Daniele Cassatella and Sykiotis, {Gerasimos P} and Richard Quinton and {De Geyter}, Christian and Mirjam Dirlewanger and Val{\'e}rie Schwitzgebel and Cole, {Trevor R} and Toogood, {Andrew A} and Kirk, {Jeremy Mw} and Lacey Plummer and Urs Albrecht and Crowley, {William F} and Moosa Mohammadi and Manuel Tena‐sempere and Vincent Prevot and Nelly Pitteloud",
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Xu, C, Messina, A, Somm, E, Miraoui, H, Kinnunen, T, Acierno, J, Niederländer, NJ, Bouilly, J, Dwyer, AA, Sidis, Y, Cassatella, D, Sykiotis, GP, Quinton, R, De Geyter, C, Dirlewanger, M, Schwitzgebel, V, Cole, TR, Toogood, AA, Kirk, JM, Plummer, L, Albrecht, U, Crowley, WF, Mohammadi, M, Tena‐sempere, M, Prevot, V & Pitteloud, N 2017, 'KLB, encoding β‐Klotho, is mutated in patients with congenital hypogonadotropic hypogonadism', EMBO Molecular Medicine, vol. 9, no. 10, pp. 1379-1397. https://doi.org/10.15252/emmm.201607376

KLB, encoding β‐Klotho, is mutated in patients with congenital hypogonadotropic hypogonadism. / Xu, Cheng; Messina, Andrea; Somm, Emmanuel; Miraoui, Hichem; Kinnunen, Tarja; Acierno, James; Niederländer, Nicolas J; Bouilly, Justine; Dwyer, Andrew A; Sidis, Yisrael; Cassatella, Daniele; Sykiotis, Gerasimos P; Quinton, Richard; De Geyter, Christian; Dirlewanger, Mirjam; Schwitzgebel, Valérie; Cole, Trevor R; Toogood, Andrew A; Kirk, Jeremy Mw; Plummer, Lacey; Albrecht, Urs; Crowley, William F; Mohammadi, Moosa; Tena‐sempere, Manuel; Prevot, Vincent; Pitteloud, Nelly.

In: EMBO Molecular Medicine, Vol. 9, No. 10, 01.08.2017, p. 1379-1397.

Research output: Contribution to journalArticle

TY - JOUR

T1 - KLB, encoding β‐Klotho, is mutated in patients with congenital hypogonadotropic hypogonadism

AU - Xu, Cheng

AU - Messina, Andrea

AU - Somm, Emmanuel

AU - Miraoui, Hichem

AU - Kinnunen, Tarja

AU - Acierno, James

AU - Niederländer, Nicolas J

AU - Bouilly, Justine

AU - Dwyer, Andrew A

AU - Sidis, Yisrael

AU - Cassatella, Daniele

AU - Sykiotis, Gerasimos P

AU - Quinton, Richard

AU - De Geyter, Christian

AU - Dirlewanger, Mirjam

AU - Schwitzgebel, Valérie

AU - Cole, Trevor R

AU - Toogood, Andrew A

AU - Kirk, Jeremy Mw

AU - Plummer, Lacey

AU - Albrecht, Urs

AU - Crowley, William F

AU - Mohammadi, Moosa

AU - Tena‐sempere, Manuel

AU - Prevot, Vincent

AU - Pitteloud, Nelly

PY - 2017/8/1

Y1 - 2017/8/1

N2 - Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic form of isolated gonadotropin‐releasing hormone (GnRH) deficiency caused by mutations in > 30 genes. Fibroblast growth factor receptor 1 (FGFR1) is the most frequently mutated gene in CHH and is implicated in GnRH neuron development and maintenance. We note that a CHH FGFR1 mutation (p.L342S) decreases signaling of the metabolic regulator FGF21 by impairing the association of FGFR1 with β‐Klotho (KLB), the obligate co‐receptor for FGF21. We thus hypothesized that the metabolic FGF21/KLB/FGFR1 pathway is involved in CHH. Genetic screening of 334 CHH patients identified seven heterozygous loss‐of‐function KLB mutations in 13 patients (4%). Most patients with KLB mutations (9/13) exhibited metabolic defects. In mice, lack of Klb led to delayed puberty, altered estrous cyclicity, and subfertility due to a hypothalamic defect associated with inability of GnRH neurons to release GnRH in response to FGF21. Peripheral FGF21 administration could indeed reach GnRH neurons through circumventricular organs in the hypothalamus. We conclude that FGF21/KLB/FGFR1 signaling plays an essential role in GnRH biology, potentially linking metabolism with reproduction.

AB - Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic form of isolated gonadotropin‐releasing hormone (GnRH) deficiency caused by mutations in > 30 genes. Fibroblast growth factor receptor 1 (FGFR1) is the most frequently mutated gene in CHH and is implicated in GnRH neuron development and maintenance. We note that a CHH FGFR1 mutation (p.L342S) decreases signaling of the metabolic regulator FGF21 by impairing the association of FGFR1 with β‐Klotho (KLB), the obligate co‐receptor for FGF21. We thus hypothesized that the metabolic FGF21/KLB/FGFR1 pathway is involved in CHH. Genetic screening of 334 CHH patients identified seven heterozygous loss‐of‐function KLB mutations in 13 patients (4%). Most patients with KLB mutations (9/13) exhibited metabolic defects. In mice, lack of Klb led to delayed puberty, altered estrous cyclicity, and subfertility due to a hypothalamic defect associated with inability of GnRH neurons to release GnRH in response to FGF21. Peripheral FGF21 administration could indeed reach GnRH neurons through circumventricular organs in the hypothalamus. We conclude that FGF21/KLB/FGFR1 signaling plays an essential role in GnRH biology, potentially linking metabolism with reproduction.

KW - Beta-klotho

KW - Congenital hypogonadotropic hypogonadism

KW - Fibroblast growth factor 21

KW - Fibroblast growth factor receptor 1

UR - http://embomolmed.embopress.org/

U2 - 10.15252/emmm.201607376

DO - 10.15252/emmm.201607376

M3 - Article

VL - 9

SP - 1379

EP - 1397

JO - EMBO Molecular Medicine

T2 - EMBO Molecular Medicine

JF - EMBO Molecular Medicine

SN - 1757-4676

IS - 10

ER -