title: Loss-of-function mutations in IGSF1 cause an X-linked syndrome of central hypothyroidism and testicular enlargement.
abstract: Congenital central hypothyroidism occurs either in isolation or in conjunction with other pituitary hormone deficits. Using exome and candidate gene sequencing, we identified 8 distinct mutations and 2 deletions in IGSF1 in males from 11 unrelated families with central hypothyroidism, testicular enlargement and variably low prolactin concentrations. IGSF1 is a membrane glycoprotein that is highly expressed in the anterior pituitary gland, and the identified mutations impair its trafficking to the cell surface in heterologous cells. Igsf1-deficient male mice show diminished pituitary and serum thyroid-stimulating hormone (TSH) concentrations, reduced pituitary thyrotropin-releasing hormone (TRH) receptor expression, decreased triiodothyronine concentrations and increased body mass. Collectively, our observations delineate a new X-linked disorder in which loss-of-function mutations in IGSF1 cause central hypothyroidism, likely secondary to an associated impairment in pituitary TRH signaling.
authors.affiliation: Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Yu
authors.initials: Y
authors.lastname: Sun
authors.forename: Beata
authors.initials: B
authors.lastname: Bak
authors.forename: Nadia
authors.initials: N
authors.lastname: Schoenmakers
authors.forename: A S Paul
authors.initials: AS
authors.lastname: van Trotsenburg
authors.forename: Wilma
authors.initials: W
authors.lastname: Oostdijk
authors.forename: Peter
authors.initials: P
authors.lastname: Voshol
authors.forename: Emma
authors.initials: E
authors.lastname: Cambridge
authors.forename: Jacqueline K
authors.initials: JK
authors.lastname: White
authors.forename: Paul
authors.initials: P
authors.lastname: le Tissier
authors.forename: S Neda Mousavy
authors.initials: SN
authors.lastname: Gharavy
authors.forename: Juan P
authors.initials: JP
authors.lastname: Martinez-Barbera
authors.forename: Wilhelmina H
authors.initials: WH
authors.lastname: Stokvis-Brantsma
authors.forename: Thomas
authors.initials: T
authors.lastname: Vulsma
authors.forename: Marlies J
authors.initials: MJ
authors.lastname: Kempers
authors.forename: Luca
authors.initials: L
authors.lastname: Persani
authors.forename: Irene
authors.initials: I
authors.lastname: Campi
authors.forename: Marco
authors.initials: M
authors.lastname: Bonomi
authors.forename: Paolo
authors.initials: P
authors.lastname: Beck-Peccoz
authors.forename: Hongdong
authors.initials: H
authors.lastname: Zhu
authors.forename: Timothy M E
authors.initials: TM
authors.lastname: Davis
authors.forename: Anita C S
authors.initials: AC
authors.lastname: Hokken-Koelega
authors.forename: Daria Gorbenko
authors.initials: DG
authors.lastname: Del Blanco
authors.forename: Jayanti J
authors.initials: JJ
authors.lastname: Rangasami
authors.forename: Claudia A L
authors.initials: CA
authors.lastname: Ruivenkamp
authors.forename: Jeroen F J
authors.initials: JF
authors.lastname: Laros
authors.forename: Marjolein
authors.initials: M
authors.lastname: Kriek
authors.forename: Sarina G
authors.initials: SG
authors.lastname: Kant
authors.forename: Cathy A J
authors.initials: CA
authors.lastname: Bosch
authors.forename: Nienke R
authors.initials: NR
authors.lastname: Biermasz
authors.forename: Natasha M
authors.initials: NM
authors.lastname: Appelman-Dijkstra
authors.forename: Eleonora P
authors.initials: EP
authors.lastname: Corssmit
authors.forename: Guido C J
authors.initials: GC
authors.lastname: Hovens
authors.forename: Alberto M
authors.initials: AM
authors.lastname: Pereira
authors.forename: Johan T
authors.initials: JT
authors.lastname: den Dunnen
authors.forename: Michael G
authors.initials: MG
authors.lastname: Wade
authors.forename: Martijn H
authors.initials: MH
authors.lastname: Breuning
authors.forename: Raoul C
authors.initials: RC
authors.lastname: Hennekam
authors.forename: Krishna
authors.initials: K
authors.lastname: Chatterjee
authors.forename: Mehul T
authors.initials: MT
authors.lastname: Dattani
authors.forename: Jan M
authors.initials: JM
authors.lastname: Wit
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Bernard
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D003409:Congenital Hypothyroidism / Q000235:genetics*; D059472:Exome; D005296:Ferrous Compounds; D040181:Genetic Diseases, X-Linked / Q000235:genetics*; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics*; D007223:Infant; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D000075163:Metallocenes; D051379:Mice; D008875:Middle Aged; D009154:Mutation; D010902:Pituitary Gland / Q000378:metabolism / Q000473:pathology; D011388:Prolactin / Q000097:blood; D018025:Receptors, Thyrotropin-Releasing Hormone / Q000096:biosynthesis; D017422:Sequence Analysis, DNA; D013577:Syndrome; D013733:Testicular Diseases / Q000235:genetics*; D013737:Testis / Q000033:anatomy & histology / Q000473:pathology; D013972:Thyrotropin / Q000097:blood; D014284:Triiodothyronine / Q000032:analysis; D055815:Young Adult
chemical_list: D005296:Ferrous Compounds; C112314:IGSF1 protein, human; D007136:Immunoglobulins; D008565:Membrane Proteins; D000075163:Metallocenes; D018025:Receptors, Thyrotropin-Releasing Hormone; D014284:Triiodothyronine; C009711:EX 10-478; D011388:Prolactin; D013972:Thyrotropin