Alternative titles; symbols
HGNC Approved Gene Symbol: FAM111A
SNOMEDCT: 722109008;
Cytogenetic location: 11q12.1 Genomic coordinates (GRCh38) : 11:59,142,856-59,155,039 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q12.1 | Gracile bone dysplasia | 602361 | Autosomal dominant | 3 |
| Kenny-Caffey syndrome, type 2 | 127000 | Autosomal dominant | 3 |
By sequencing clones obtained from a size-fractionated fetal brain cDNA library, Nagase et al. (2001) cloned FAM111A, which they designated KIAA1895. The transcript contains several repetitive elements, and the deduced protein contains 628 amino acids. RT-PCR ELISA detected highest FAM111A expression in adult spleen, followed by adult kidney, lung, ovary, liver, and pancreas and fetal liver. Much lower expression was detected in adult heart, skeletal muscle, and testis and in all fetal and adult brain regions examined.
Fine et al. (2012) reported that the 611-amino acid FAM11A protein contains a C-terminal trypsin-like serine peptidase domain that includes the conserved catalytic triad of histidine, aspartate, and serine. FAM111A localized to both nuclear and cytoplasmic fractions of U2OS osteosarcoma cells. In synchronized T98G glioblastoma cells, FAM11A mRNA and protein expression was lowest at G0 phase of the cell cycle and peaked as cells progressed toward G2/M phase.
Hartz (2013) mapped the FAM111A gene to chromosome 11q12.1 based on an alignment of the FAM111A sequence (GenBank AK025319) with the genomic sequence (GRCh37).
The C-terminal domain of large T antigen (LT) of simian virus-40 (SV40) is required for host range restriction and adenovirus helper functions of SV40. Fine et al. (2012) found that the C-terminal half of FAM111A interacted with the C-terminal domain of LT and functioned as a host range restriction factor.
In 5 patients with autosomal dominant Kenny-Caffey syndrome (KCS2; 127000) and 5 patients with gracile bone dysplasia (GCLEB; 602361), Unger et al. (2013) identified heterozygous mutations in the FAM111A gene (see 615292.0001-615292.0006). In the 7 families in which DNA was available from both parents, the mutations were confirmed to have arisen de novo. The authors concluded that KCS2 and gracile bone dysplasia represent allelic disorders of differing severity.
In 4 unrelated patients with Kenny-Caffey syndrome (KCS2; 127000), Unger et al. (2013) identified heterozygosity for a c.1706G-A transition in the FAM111A gene, resulting in an arg569-to-his (R569H) substitution. The mutation was not found in the 1000 Genomes Project or NHLBI Exome Variant Server databases. The patients included a 40-year-old Swiss woman, a 17-year-old Indian boy, a 10-year-old German boy, and a 6-month-old Italian girl. In the 2 patients for whom DNA was available from both parents, the mutation was confirmed to have arisen de novo. Hypocalcemia was noted in 3 of the 4 patients; other features included hypermetropic and defective dentition. The oldest patient also had cataracts, hypoacusis, and a high-pitched voice.
In 3 unrelated Japanese patients with KCS2, Isojima et al. (2014) identified heterozygosity for the R569H mutation in the FAM111A gene. The mutation segregated with the disorder in all 3 families. Isojima et al. (2014) identified the mutation in an additional unrelated patient.
In 2 male infants with gracile bone dysplasia (GCLEB; 602361), 1 Swedish and 1 Italian, who died at 3 days and 25 days of life, respectively, Unger et al. (2013) identified heterozygosity for a de novo 3-bp deletion (1026_1028delTTC) in the FAM111A gene, resulting in deletion of a serine residue at position 342 (S342X). The mutation was not found in either set of parents, or in the 1000 Genomes Project or NHLBI Exome Variant Server databases. Both patients were hypocalcemic; additional features included micropenis in both, and 1 was noted to be asplenic at autopsy, whereas in the other patient the spleen was present.
In a 7-year-old Indian boy with Kenny-Caffey syndrome (KCS2; 127000), Unger et al. (2013) identified heterozygosity for a c.1531T-C transition in the FAM111A gene, resulting in a tyr511-to-his (Y511H) substitution at a phylogenetically conserved residue. The mutation was not present in the 1000 Genomes Project or NHLBI Exome Variant Server databases. Additional features in the patient included open anterior fontanel, defective dentition, and high-pitched voice.
In a 20-month-old Swedish boy with gracile bone dysplasia (GCLEB; 602361), Unger et al. (2013) identified heterozygosity for a de novo c.1583A-G transition in the FAM111A gene, resulting in an asp528-to-gly (D528G) substitution at a phylogenetically conserved residue. The mutation was not found in either of his parents or in the 1000 Genomes Project or NHLBI Exome Variant Server databases. In addition to hypocalcemia and severe short stature, the patient displayed hydrocephalus requiring a shunt, seizures, micropenis, bone fragility, severe failure to thrive, hepatopathy, and developmental delay.
In a Chilean infant who died at 2 months of age with gracile bone dysplasia (GCLEB; 602361), Unger et al. (2013) identified heterozygosity for a de novo c.1012A-G transition in the FAM111A gene, resulting in a thr338-to-ala (T338A) substitution at a phylogenetically conserved residue. The mutation was not found in either of his parents or in the 1000 Genomes Project or NHLBI Exome Variant Server databases. In addition to hypocalcemia and short stature, the patient displayed microphthalmia and had a femoral fracture at birth.
In a Japanese infant who died at 8 months of age with gracile bone dysplasia (GCLEB; 602361), Unger et al. (2013) identified heterozygosity for a de novo c.1579C-A transversion in the FAM111A gene, resulting in a pro527-to-thr (P527T) substitution at a phylogenetically conserved residue. The mutation was not found in either of his parents or in the 1000 Genomes Project or NHLBI Exome Variant Server databases. In addition to hypocalcemia and short stature, the patient displayed hydrocephalus and micropenis.
Fine, D. A., Rozenblatt-Rosen, O., Padi, M., Korkhin, A., James, R. L., Adelmant, G., Yoon, R., Guo, L., Berrios, C., Zhang, Y., Calderwood, M. A., Velmurgan, S., and 9 others. Identification of FAM111A as an SV40 host range restriction and adenovirus helper factor. PLoS Pathog. 8: e1002949, 2012. Note: Electronic Article. [PubMed: 23093934] [Full Text: https://doi.org/10.1371/journal.ppat.1002949]
Hartz, P. A. Personal Communication. Baltimore, Md. 6/26/2013.
Isojima, T., Doi, K., Mitsui, J., Oda, Y., Tokuhiro, E., Yasoda, A., Yorijuji, T., Horikawa, R., Yoshimura, J., Ishiura, H., Morishita, S., Tsuji, S., Kitanaka, S. A recurrent de novo FAM111A mutation causes Kenny-Caffey syndrome type 2. J. Bone Miner. Res. 29: 992-998, 2014. [PubMed: 23996431] [Full Text: https://doi.org/10.1002/jbmr.2091]
Nagase, T., Kikuno, R., Ohara, O. Prediction of the coding sequences of unidentified human genes. XXI. The complete sequences of 60 new cDNA clones from brain which code for large proteins. DNA Res. 8: 179-187, 2001. [PubMed: 11572484] [Full Text: https://doi.org/10.1093/dnares/8.4.179]
Unger, S., Gorna, M. W., Le Bechec, A., Do Vale-Pereira, S., Bedeschi, M. F., Geiberger, S., Grigelioniene, G., Horemuzova, E., Lalatta, F., Lausch, E., Magnani, C., Nampoorthiri, S., and 12 others. FAM111A mutations result in hypoparathyroidism and impaired skeletal development. Am. J. Hum. Genet. 92: 990-995, 2013. [PubMed: 23684011] [Full Text: https://doi.org/10.1016/j.ajhg.2013.04.020]