Putative gain of function mutations in FAM111A result in Kenny-Caffey syndrome and Osteocraniostenosis: identification of an upstream regulator of the PTH axis. S. Unger1,2, M. W. Gorna3, A. Le Bechec4, S. Do Vale-Pereira2, F. Bedeschi5, S. Geiberger6, G. Grigelioniene7, E. Horemuzova8, F. Lalatta5, E. Lausch9, C. Magnani10, S. Nampoothiri11, G. Nishimura12, D. Petrella13, F. Rojas-Ringeling14, A. Utsunomiya15, B. Zabel9, S. Pradervand16, K. Harshman16, B. Campos-Xavier2, L. Bonafé2, G. Superti-Furga3, B. Stevenson4, A. Superti-Furga2 1) Service de Génétique Médicale, CHUV / University of Lausanne, Lausanne, Switzerland; 2) Dept of Pediatrics, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland; 3) CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria; 4) Vital-IT - High Performance Computing Center, Swiss Institute of Bioinformatics, Univ. of Lausanne, Lausanne, Switzerland; 5) Clinical Genetic Unit, Fondazione Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milano, Italy; 6) Department of Pediatric Radiology, Astrid Lindgrens Barnsjukhus, Karolinska Sjukhuset, Stockholm, Sweden; 7) Dept of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; 8) Dept of Women's and Children's Health, Karolinska Institutet, Pediatric Endocrinology Unit, Karolinska Hospital, Stockholm, Sweden; 9) 7 Paediatric Genetics Division, Centre for Paediatrics and Adolescent Medicine, Freiburg University Hospital, Freiburg, Germany; 10) Dept of Neonatal Intensive Care Unit, University of Parma, Parma, Italy; 11) Amrita Institute of Medical Sciences & Research Center, Dept of Pediatric Genetics, AIMS Ponekkara, Cochin, Kerala, India; 12) Dept of Radiology and Medical Imaging, Tokyo Metropolitan Kiyose Childrens Hospital, Kiyose, Japan; 13) Dept of Pathology, Niguarda Ca' Granda Hospital, Milano, Italy; 14) Genética Clínica, Hospital Clínico Universidad de Chile, Santiago, Chile; 15) Dept of Pediatrics, Graduate School of Biomedical Science, Hiroshima University, Hiroshima, Japan; 16) Genomic Technologies Facility, Faculty of Biology and Medicine, Univ. of Lausanne, Lausanne, Switzerland.

   The Kenny-Caffey syndrome (KCS; MIM 127000) and the more severe Osteocraniostenosis (OCS; MIM 602361) are conditions characterized by impaired skeletal development with small and dense bones, short stature, and primary hypoparathyroidism with hypocalcemia. While dominant transmission of KCS has been reported, including the mother and son originally described by Kenny, Linarelli and Caffey, OCS is usually lethal and has only been observed in sporadic cases. We speculated that KCS and OCS might share a common genetic etiology, and we studied a cohort of individuals with KCS or OCS with whole exome and direct gene sequencing. All ten individuals studied had heterozygous mutations in the gene FAM111A; one mutation was identified in four unrelated patients with KCS, and another one in two unrelated patients with OCS, and all occurred de novo in affected individuals (Unger et al, AJHG, in press, June 2013). Thus, OCS and KCS are allelic disorders, and FAM111A appears to be crucial to a pathway that governs PTH production, calcium homeostasis, and skeletal growth. What is the link between FAM111A and the parathyroid hormone (PTH) axis? FAM111A codes for a 611 amino acid protein with homology to trypsin-like peptidases that is localized to the cytoplasm and the nucleus. While its native function is unknown, it has been found to bind to the large T-antigen of SV40 and to restrict viral replication. Putative loss of function mutations have been observed in public databases, apparently without clinical correlates. Molecular modeling of FAM111A shows that residues affected by OCS/KS mutations do not map close to the active site, but are clustered at, or close to, a restricted region on its surface. This suggests that rather than impairing the catalytic activity of FAM111A, the KCS/OCS mutations may affect the interaction with other proteins. Based on the published data on interaction between FAM111A and SV40-LT and on the protein modeling results, we propose a model in which FAM111A activity is physiologically regulated by binding to an inhibitor; in the presence of KCS/OCS mutations, binding is impaired and activity is unrestricted. How FAM111A gain of function would result in the disruption of PTH activation remains to be determined. However, pinpointing the molecular defect in KCS and OCS upstream of the PTH system itself opens the possibility of therapeutic approaches using PTH analogues to treat chronic hypocalcemia and impaired bone growth.

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