Alternative titles; symbols
HGNC Approved Gene Symbol: AFF4
SNOMEDCT: 764455002;
Cytogenetic location: 5q31.1 Genomic coordinates (GRCh38) : 5:132,875,395-132,963,634 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q31.1 | CHOPS syndrome | 616368 | Autosomal dominant | 3 |
The AFF4 gene encodes a scaffold protein that functions as a core component of the super elongation complex (SEC), which is involved in transcriptional regulation during embryogenesis (summary by Izumi et al., 2015).
Infantile acute lymphoblastic leukemia (ALL) with rearrangements of the MLL gene (159555) is characterized by early pre-B phenotype and poor treatment outcome. Taki et al. (1999) studied a 4-month-old girl with the diagnosis of ALL. Leukemic cells were characterized cytogenetically as ins(5;11)(q31;q13q23), i(17q). By molecular studies, Taki et al. (1999) identified a gene on 5q31 as a fusion partner of the MLL gene. The AF5q31 gene (GenBank AF197927), so termed for 'ALL1-fused gene partner from 5q31,' encodes a protein of 1,163 amino acids, is located in the vicinity of the cytokine cluster region of 5q31, and contains at least 16 exons. The AF5q31 gene was expressed in fetal heart, lung, and brain at relatively high levels and in fetal liver at a low level, but the expression in these tissues was decreased in adults. The AF5q31 protein was homologous to AF4-related proteins, including AF4 (159557), LAF4 (601464), and FMR2 (309548). The AF5q31 and AF4 proteins had 3 homologous regions, including the transactivation domain of AF4, and the breakpoint of AF5q31 was located within the region homologous to the transactivation domain of AF4. Furthermore, the clinical features of the patient with the MLL-AF5q31 fusion transcript, characterized by the early pre-B phenotype and poor outcome, were similar to those of patients having MLL-AF4 chimeric transcripts. Taki et al. (1999) suggested that these findings may indicate that AF5q31 and AF4 defines a new family particularly involved in the pathogenesis of 11q23-associated ALL.
By Northern blot analysis, Urano et al. (2005) detected high Af5q31 expression in adult mouse testis, with lower levels in several other adult mouse tissues. Immunohistochemical analysis of mouse testis revealed that Af5q31 was expressed preferentially in Sertoli cells, weakly in germ cells, and barely in Leydig cells.
Taki et al. (1999) determined that the AFF4 gene maps to chromosome 5q31.
Izumi et al. (2015) found a direct interaction between the SEC, cohesin, and phosphorylated RNA polymerase II (RNAP2).
In 3 unrelated children with cognitive impairment, coarse facies, heart defects, obesity, pulmonary involvement, short stature, and skeletal dysplasia (CHOPS; 616368), Izumi et al. (2015) identified 3 different de novo heterozygous missense mutations in the AFF4 gene (604417.0001-604417.0003), all of which affected conserved residues in the ALF homology domain. The mutations were found by whole-exome sequencing. In vitro functional expression studies showed that all the mutations resulted in decreased degradation of AFF4 by the ubiquitin E3 ligase SIAH1 (602212) compared to wildtype. All 3 patient cell lines showed upregulation of MYC (190080) and 2 showed upregulation of JUN (165160), both of which are direct transcriptional targets of AFF4. Transcriptome analysis of patient cell lines showed upregulation of several genes, consistent with a gain-of-function effect, and overall changes in gene regulation were similar to that observed in patients with Cornelia de Lange syndrome (see, e.g., CDLS1, 122470). Chromatin immunoprecipitation analysis showed a correlation between RNA regulation and chromatin binding levels of paused RNAP2 in both CDLS and CHOPS.
Urano et al. (2005) found that loss of Af5q31 resulted in a 55% decrease in Af5q31 -/- mouse neonates relative to wildtype and heterozygous neonates, based on the mendelian ratio. Moreover, 71% of Af5q31 -/- neonates died as early as 12 to 24 hours postpartum. Histochemical analysis showed that lethality of Af5q31 -/-neonates was caused, at least in part, by severely shrunken alveoli of lung. Analysis during gestation revealed that Af5q31 was important for embryonic development. Af5q31 -/- males were infertile due to failure of spermatogenesis, whereas females were fertile. Af5q31 regulated spermiogenesis through modulation of testis-specific gene expression in Sertoli cells. TUNEL assays demonstrated that Af5q31 was essential for both differentiation and survival of germ cells, and consequently, loss of Af5q31 led to germ cell apoptosis in Af5q31 -/- mice.
In a boy with cognitive impairment, coarse facies, heart defects, obesity, pulmonary involvement, short stature, and skeletal dysplasia (CHOPS; 616368), Izumi et al. (2015) identified a de novo heterozygous c.760A-G transition in the AFF4 gene, resulting in a thr254-to-ala (T254A) substitution at a highly conserved residue in the ALF homology domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in in-house controls.
In a girl with cognitive impairment, coarse facies, heart defects, obesity, pulmonary involvement, short stature, and skeletal dysplasia (CHOPS; 616368), Izumi et al. (2015) identified a de novo heterozygous c.761C-G transversion in the AFF4 gene, resulting in a thr254-to-ser (T254S) substitution at a highly conserved residue in the ALF homology domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in in-house controls.
In a girl with cognitive impairment, coarse facies, heart defects, obesity, pulmonary involvement, short stature, and skeletal dysplasia (CHOPS; 616368), Izumi et al. (2015) identified a de novo heterozygous c.772C-T transition in the AFF4 gene, resulting in an arg258-to-trp (R258W) substitution at a highly conserved residue in the ALF homology domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in in-house controls.
Izumi, K., Nakato, R., Zhang, Z., Edmondson, A. C., Noon, S., Dulik, M. C., Rajagopalan, R., Venditti, C. P., Gripp, K., Samanich, J., Zackai, E. H., Deardorff, M. A., and 10 others. Germline gain-of-function mutations in AFF4 cause a developmental syndrome functionally linking the super elongation complex and cohesin. Nature Genet. 47: 338-344, 2015. [PubMed: 25730767] [Full Text: https://doi.org/10.1038/ng.3229]
Taki, T., Kano, H., Taniwaki, M., Sako, M., Yanagisawa, M., Hayashi, Y. AF5q31, a newly identified AF4-related gene, is fused to MLL in infant acute lymphoblastic leukemia with ins(5;11)(q31;q31q23). Proc. Nat. Acad. Sci. 96: 14535-14540, 1999. [PubMed: 10588740] [Full Text: https://doi.org/10.1073/pnas.96.25.14535]
Urano, A., Endoh, M., Wada, T., Morikawa, Y., Itoh, M., Kataoka, Y., Taki, T., Akazawa, H., Nakajima, H., Komuro, I., Yoshida, N., Hayashi, Y., Handa, H., Kitamura, T., Nosaka, T. Infertility with defective spermiogenesis in mice lacking AF5q31, the target of chromosomal translocation in human infant leukemia. Molec. Cell. Biol. 25: 6834-6845, 2005. [PubMed: 16024815] [Full Text: https://doi.org/10.1128/MCB.25.15.6834-6845.2005]