TY - JOUR
T1 - FAM111A mutations result in hypoparathyroidism and impaired skeletal development
AU - Unger, Sheila
AU - Górna, Maria W.
AU - Le Béchec, Antony
AU - Do Vale-Pereira, Sonia
AU - Bedeschi, Maria Francesca
AU - Geiberger, Stefan
AU - Grigelioniene, Giedre
AU - Horemuzova, Eva
AU - Lalatta, Faustina
AU - Lausch, Ekkehart
AU - Magnani, Cinzia
AU - Nampoothiri, Sheela
AU - Nishimura, Gen
AU - Petrella, Duccio
AU - Rojas-Ringeling, Francisca
AU - Utsunomiya, Akari
AU - Zabel, Bernhard
AU - Pradervand, Sylvain
AU - Harshman, Keith
AU - Campos-Xavier, Belinda
AU - Bonafé, Luisa
AU - Superti-Furga, Giulio
AU - Stevenson, Brian
AU - Superti-Furga, Andrea
PY - 2013/6/6
Y1 - 2013/6/6
N2 - 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.
AB - 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.
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U2 - 10.1016/j.ajhg.2013.04.020
DO - 10.1016/j.ajhg.2013.04.020
M3 - Article
C2 - 23684011
AN - SCOPUS:84878878820
VL - 92
SP - 990
EP - 995
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 6
ER -