title: FAM111A mutations result in hypoparathyroidism and impaired skeletal development.
abstract: Kenny-Caffey syndrome (KCS) and the similar but more severe osteocraniostenosis (OCS) are genetic conditions characterized by impaired skeletal development with small and dense bones, short stature, and primary hypoparathyroidism with hypocalcemia. We studied five individuals with KCS and five with OCS and found that all of them had heterozygous mutations in FAM111A. One mutation was identified in four unrelated individuals with KCS, and another one was identified in two unrelated individuals with OCS; all occurred de novo. Thus, OCS and KCS are allelic disorders of different severity. FAM111A codes for a 611 amino acid protein with homology to trypsin-like peptidases. Although FAM111A has been found to bind to the large T-antigen of SV40 and restrict viral replication, its native function is unknown. Molecular modeling of FAM111A shows that residues affected by KCS and OCS mutations do not map close to the active site but are clustered on a segment of the protein and are at, or close to, its outer surface, suggesting that the pathogenesis involves the interaction with as yet unidentified partner proteins rather than impaired catalysis. FAM111A appears to be crucial to a pathway that governs parathyroid hormone production, calcium homeostasis, and skeletal development and growth.
authors.affiliation: Department of Pediatrics, Lausanne University Hospital, University of Lausanne, 1011 Lausanne, Switzerland; Medical Genetics Service, Lausanne University Hospital, University of Lausanne, 1011 Lausanne, Switzerland.
authors.forename: Sheila
authors.initials: S
authors.lastname: Unger
authors.forename: Maria W
authors.initials: MW
authors.lastname: Górna
authors.forename: Antony
authors.initials: A
authors.lastname: Le Béchec
authors.forename: Sonia
authors.initials: S
authors.lastname: Do Vale-Pereira
authors.forename: Maria Francesca
authors.initials: MF
authors.lastname: Bedeschi
authors.forename: Stefan
authors.initials: S
authors.lastname: Geiberger
authors.forename: Giedre
authors.initials: G
authors.lastname: Grigelioniene
authors.forename: Eva
authors.initials: E
authors.lastname: Horemuzova
authors.forename: Faustina
authors.initials: F
authors.lastname: Lalatta
authors.forename: Ekkehart
authors.initials: E
authors.lastname: Lausch
authors.forename: Cinzia
authors.initials: C
authors.lastname: Magnani
authors.forename: Sheela
authors.initials: S
authors.lastname: Nampoothiri
authors.forename: Gen
authors.initials: G
authors.lastname: Nishimura
authors.forename: Duccio
authors.initials: D
authors.lastname: Petrella
authors.forename: Francisca
authors.initials: F
authors.lastname: Rojas-Ringeling
authors.forename: Akari
authors.initials: A
authors.lastname: Utsunomiya
authors.forename: Bernhard
authors.initials: B
authors.lastname: Zabel
authors.forename: Sylvain
authors.initials: S
authors.lastname: Pradervand
authors.forename: Keith
authors.initials: K
authors.lastname: Harshman
authors.forename: Belinda
authors.initials: B
authors.lastname: Campos-Xavier
authors.forename: Luisa
authors.initials: L
authors.lastname: Bonafé
authors.forename: Giulio
authors.initials: G
authors.lastname: Superti-Furga
authors.forename: Brian
authors.initials: B
authors.lastname: Stevenson
authors.forename: Andrea
authors.initials: A
authors.lastname: Superti-Furga
mesh_terms: D000015:Abnormalities, Multiple / Q000000981:diagnostic imaging / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D000293:Adolescent; D000328:Adult; D001848:Bone Diseases, Developmental / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D002648:Child; D019465:Craniofacial Abnormalities / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D004392:Dwarfism / Q000000981:diagnostic imaging / Q000235:genetics* / Q000401:mortality; D056726:Genetic Association Studies; D006579:Heterozygote; D006801:Humans; D006958:Hyperostosis, Cortical, Congenital / Q000000981:diagnostic imaging / Q000235:genetics* / Q000401:mortality; D006996:Hypocalcemia / Q000000981:diagnostic imaging / Q000235:genetics* / Q000401:mortality; D007011:Hypoparathyroidism / Q000000981:diagnostic imaging / Q000235:genetics* / Q000401:mortality; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D020125:Mutation, Missense; D010281:Parathyroid Hormone / Q000172:deficiency; D011859:Radiography; D011991:Receptors, Virus / Q000235:genetics*
chemical_list: C579415:FAM111A protein, human; D010281:Parathyroid Hormone; D011991:Receptors, Virus