Other entities represented in this entry:
HGNC Approved Gene Symbol: TMEM185A
Cytogenetic location: Xq28 Genomic coordinates (GRCh38): X:149,596,556-149,631,792 (from NCBI)
The FAM11A gene originates from the CpG island of the fragile site FRAXF and contains the FRAXF CGG repeat in its 5-prime untranslated region (Shaw et al., 2002). Expansion of the FRAXF CGG repeat and consequent methylation of the CpG island results in transcriptional silencing of the FAM11A gene.
Fragile Site FRAXF
In addition to FRAXA (see 309550) and FRAXE (309548), Hirst et al. (1993) described a third folate-sensitive fragile site on the distal end of Xq. FRAXA and FRAXE contain expanded, hypermethylated, and unstable CGG repeats within CpG islands. Parrish et al. (1994) reported the isolation of similar sequences responsible for FRAXF. In 5 individuals who exhibited fragile sites in distal Xq, a 5-kb EcoRI fragment derived from a cosmid coincident with the cytogenetic anomaly detected expanded, methylated, and unstable sequences; these individuals had normal repeat lengths at both FRAXA and FRAXE. PCR and sequence analysis of chromosomes from the general population indicated that the repeat is polymorphic (6 to 29 triplets) and is stable upon transmission. No direct correlation of the cytogenetic fragile site with mental retardation or with expansion of the repeats was found. Thus, like FRA16A, FRAXF may not disturb gene expression in any phenotypically observable manner. On the other hand, it is likely that any gene in the vicinity of FRAXF would be transcriptionally repressed in an individual expressing the fragile site.
Ritchie et al. (1994) cloned the FRAXF site and demonstrated that it involves the expansion of a (GCCGTC)n(GCC)n compound array. PCR analyses across the repeat of normal individuals showed that the number of triplets in the array ranged from 12 to 26 and the most common allele consisted of 14 triplet units. Sequencing analyses showed that 95% of normal individuals have 3 copies of the GCCGTC motif and in these individuals, the size variation observed by PCR is due to copy number alterations in the GCC array.
FAM11A Gene
By database analysis, Shaw et al. (2002) identified FAM11A from an EST cluster encompassing the FRAXF fragile site on chromosome X. The deduced FAM11A protein contains 350 amino acids. Mouse and human FAM11A differ by 1 amino acid, and FAM11A orthologs are present in D. melanogaster and C. elegans. RT-PCR analysis with primers flanking the unstable FRAXF CGG repeat showed that the FAM11A transcript contains the repeat in its 5-prime UTR. Northern blot analysis detected near ubiquitous expression of 2 major FAM11A isoforms of 2.6 and 2.1 kb, with highest expression in heart, skeletal muscle, kidney, and placenta. EST database analysis also indicated wide tissue distribution. PCR of normal lymphoblast cDNA detected alternative splicing of exons 2, 3, 4, and 7 in FAM11A.
Shaw et al. (2002) analyzed the expression of FAM11A in transformed lymphoblasts obtained from a normal adult male with a cytogenetically and molecularly detectable CGG expansion at FRAXF. In this lymphoblastoid cell line, expansion of the CGG repeat and consequent methylation of the CpG island resulted in transcriptional silencing of the FAM11A gene. Cells treated with the demethylation agent 5-azadeoxycytidine reactivated FAM11A gene transcription.
Shaw et al. (2002) determined that the FAM11A gene contains at least 7 exons and spans about 35 kb.
By genomic sequence analysis, Shaw et al. (2002) mapped the FAM11A gene to chromosome Xq28, where it lies distal to and overlaps the FRAXF CpG island. They mapped the mouse Fam11a gene to chromosome X.
In a cytogenetically positive male with developmental delay, Ritchie et al. (1994) found that the FRAXF (GCCGTC)n(GCC)n compound array was expanded by more than 900 triplets, and the adjacent CpG-rich region was methylated. The array was also expanded in cytogenetically positive carrier females from the family originally used to define the FRAXF site (Hirst et al., 1993).
Barnicoat et al. (1997) identified a family with FRAXF expansion by fluorescence in situ hybridization.
Knight et al. (1996) noted that of the 8 individuals in their study cytogenetically positive (banded chromosomes) for a fragile site in Xq27.3-q28, 3 had an expansion of the FRAXF GCC repeat. They summarized that in contrast to FRAXE, a higher proportion of FRAXF patients had been described in whom the cytogenetic expression had no apparent association with mental impairment (e.g., Ritchie et al., 1994). This suggested to Knight et al. (1996) that ascertainment bias may have been involved in identification of the mentally impaired FRAXF individuals presented in this study. They suggested that more complex scenarios involving mosaicisms of copy number, methylation, or tissue differences had yet to be ruled out.
Strelnikov et al. (1999) stated that though originally found in mentally retarded patients, FRAXF is considered a rare fragile site with no associated phenotype.
Barnicoat, A. J., Wang, Q., Turk, J., Green, E., Mathew, C. G., Flynn, G., Buckle, V., Hirst, M., Davies, K., Bobrow, M. Clinical, cytogenetic, and molecular analysis of three families with FRAXE. J. Med. Genet. 34: 13-17, 1997. [PubMed: 9032643] [Full Text: https://doi.org/10.1136/jmg.34.1.13]
Hirst, M. C., Barnicoat, A., Flynn, G., Wang, Q., Daker, M., Buckle, V. J., Davies, K. E., Bobrow, M. The identification of a third fragile site, FRAXF, in Xq27-q28 distal to both FRAXA and FRAXE. Hum. Molec. Genet. 2: 197-200, 1993. [PubMed: 8499907] [Full Text: https://doi.org/10.1093/hmg/2.2.197]
Knight, S. J. L., Ritchie, R. J., Chakrabarti, L., Cross, G., Taylor, G. R., Mueller, R. F., Hurst, J., Paterson, J., Yates, J. R. W., Dow, D. J., Davies, K. E. A study of FRAXE in mentally retarded individuals referred for fragile X syndrome (FRAXA) testing in the United Kingdom. Am. J. Hum. Genet. 58: 906-913, 1996. [PubMed: 8651274]
Parrish, J. E., Oostra, B. A., Verkerk, A. J. M. H., Richards, C. S., Reynolds, J., Spikes, A. S., Shaffer, L. G., Nelson, D. L. Isolation of a GCC repeat showing expansion in FRAXF, a fragile site distal to FRAXA and FRAXE. Nature Genet. 8: 229-235, 1994. [PubMed: 7874164] [Full Text: https://doi.org/10.1038/ng1194-229]
Ritchie, R. J., Knight, S. J. L., Hirst, M. C., Grewal, P. K., Bobrow, M., Cross, G. S., Davies, K. E. The cloning of FRAXF: trinucleotide repeat expansion and methylation at a third fragile site in distal Xqter. Hum. Molec. Genet. 3: 2115-2121, 1994. [PubMed: 7881407] [Full Text: https://doi.org/10.1093/hmg/3.12.2115]
Shaw, M. A., Chiurazzi, P., Romain, D. R., Neri, G., Gecz, J. A novel gene, FAM11A, associated with the FRAXF CpG island is transcriptionally silent in FRAXF full mutation. Europ. J. Hum. Genet. 10: 767-772, 2002. [PubMed: 12404111] [Full Text: https://doi.org/10.1038/sj.ejhg.5200881]
Strelnikov, V., Nemtsova, M., Chesnokova, G., Kuleshov, N., Zaletayev, D. A simple multiplex FRAXA, FRAXE, and FRAXF PCR assay convenient for wide screening programs. Hum. Mutat. 13: 166-169, 1999. [PubMed: 10094554] [Full Text: https://doi.org/10.1002/(SICI)1098-1004(1999)13:2<166::AID-HUMU10>3.0.CO;2-X]