Alternative titles; symbols
HGNC Approved Gene Symbol: MAFB
SNOMEDCT: 766992008;
Cytogenetic location: 20q12 Genomic coordinates (GRCh38) : 20:40,685,848-40,689,236 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 20q12 | Duane retraction syndrome 3 | 617041 | Autosomal dominant | 3 |
| Multicentric carpotarsal osteolysis syndrome | 166300 | Autosomal dominant | 3 |
MAF family members, such as MAFB, are basic region/leucine zipper transcription factors that affect transcription positively or negatively, depending on their partner proteins and the context of the target promoter (Wang et al., 1999).
Wang et al. (1999) identified the MAFB gene, which they called KRML, within a region of chromosome 20 deleted in malignant myeloid disorders. By PCR of genomic DNA, followed by screening a bone marrow cDNA library and EST database analysis, they obtained 3 full-length cDNAs that differ only in their utilization of alternate polyadenylation signals. The common deduced protein contains 323 amino acids and has a calculated molecular mass of 35.8 kD. MAFB has a pro-ser-thr-rich acidic transcription activation domain at its N terminus, followed by 2 histidine repeats, an extended homology region, a basic DNA-binding domain, and a C-terminal leucine zipper domain containing hydrophobic residues that form the zipper heptad repeats (LLLLYL). MAFB shares 84% amino acid identity with its murine homolog. Northern blot analysis detected ubiquitous expression of MAFB. A 3.0-kb transcript was expressed in all tissues analyzed, and a 1.8-kb transcript was expressed predominantly in bone marrow and skeletal muscle, with low-level expression in heart.
Wang et al. (1999) determined that the MAFB gene has a single exon and spans about 3 kb.
By sequence analysis, Wang et al. (1999) mapped the MAFB gene to chromosome 20q11.2-q13.1.
Using a yeast 2-hybrid screen and in vitro protein-binding assays, Petersen et al. (2004) demonstrated that human MAFB interacted directly with the intracellular domain (ICD) of mouse Lrp1 (107770). Mutation analysis indicated that the leucine zipper motif of MAFB was required for this interaction. Murine Mafb and the isolated ICD colocalized in the nucleus of cotransfected human embryonic kidney cells. The ICD also localized in the cytoplasm. MAFB stimulated expression of a reporter gene that was constructed with 3 upstream copies of the Maf recognition element (MARE) followed by a TATA-like promoter. Cotransfection of the Lrp1 ICD with MAFB reduced the transactivation potential of MAFB.
Garzon et al. (2006) identified MAFB as a putative target of MIRN130A (610175) and, using RT-PCR and Western blot analysis, found that MAFB mRNA and protein were upregulated during megakaryocytic differentiation. Transfection of a human megakaryocytic leukemia cell line with MIRN130A precursor reduced expression of a reporter gene containing the 3-prime UTR of MAFB, and overexpression of MIRN130A in a myelogenous leukemia cell line reduced MAFB protein levels.
Aziz et al. (2009) reported that combined deficiency for the transcription factors MafB and c-Maf enables extended expansion of mature monocytes and macrophages in culture without loss of differentiated phenotype and function. Upon transplantation, the expanded cells are nontumorigenic and contribute to functional macrophage populations in vivo. Small hairpin RNA inactivation showed that continuous proliferation of MafB/c-Maf-deficient macrophages requires concomitant upregulation of 2 pluripotent stem cell-inducing factors, KLF4 (602253) and c-Myc (190080). Aziz et al. (2009) concluded that MafB/c-Maf deficiency renders self-renewal compatible with terminal differentiation. It thus appears possible to amplify functional differentiated cells without malignant transformation or stem cell intermediates.
Multicentric Carpotarsal Osteolysis Syndrome
In 11 simplex cases and affected individuals from 2 pedigrees with multicentric carpotarsal osteolysis syndrome (MCTO; 166300), Zankl et al. (2012) identified heterozygosity for missense mutations in the MAFB gene (see, e.g., 608968.0001-608968.0006). The mutations were clustered within a 51-bp region of the single exon of MAFB. All but the 3 youngest simplex cases had renal disease, and 5 patients had undergone renal transplantation; however, because affected adults from the 2 families did not manifest renal dysfunction, Zankl et al. (2012) concluded that MAFB mutations are also responsible for MCTO in the absence of renal disease.
Duane Retraction Syndrome 3 with or without Deafness
In affected members of a family (family FA) with Duane retraction syndrome and hearing loss (DURS3; 617041), Park et al. (2016) screened the MAFB gene and identified heterozygosity for a 1-bp deletion (608968.0007). Screening of MAFP in additional probands with DURS identified 2 more DURS families with heterozygous 1-bp deletions (608968.0008-608968.0009) and 1 with a heterozygous full gene deletion (608968.0010). None of the affected individuals in the 3 additional families had hearing loss. Functional analysis suggested a threshold model for variable loss of MAFB function, with the mutation in family FA causing a dominant-negative effect, resulting in less than 50% protein function and causing both DURS and deafness, whereas the heterozygous loss-of-function mutations in the other 3 families with isolated DURS showed 50% protein function. These results were consistent with the phenotypes observed in Mafb +/- and knockout mice (see ANIMAL MODEL).
Associations Pending Confirmation
For discussion of a possible association between variation in the MAFB gene and susceptibility to nonsyndromic cleft lip/palate, see 119530.
Wang et al. (1999) noted that mutations in the murine Mafb gene are responsible for the mouse mutant Kreisler (kr), a developmental defect of the hindbrain.
Artner et al. (2007) stated that homozygous Mafb-mutant mice die at birth: kr mice of renal failure and Mafb -/- mice of central apnea. They observed that Mafb -/- mouse embryos had reduced numbers of pancreatic alpha and beta cells, whereas the total number of endocrine cells was unchanged. Production of alpha cells was delayed until embryonic day 13.5 in mutant embryos and coincident with the onset of Mafa (610303) expression.
Yu et al. (2013) developed Mafb conditional knockout (CKO) mice to avoid the early lethality and inner ear malformations of Mafb-null mice. They found that Mafb was expressed in spiral ganglion neurons (SGNs) and that expression peaked during synaptogenesis in mice. Analysis of Mafb CKO mice showed that Mafb was not required for the initial production or differentiation of SGNs. Instead, Mafb was essential for development of the auditory afferent synapse, as Mafb acted in SGN afferents to specify postsynaptic differentiation of ribbon synapses. Despite normal intrinsic membrane and firing properties in SGNs, SGNs failed to develop normal postsynaptic densities (PSDs) in Mafb CKO mice, leading to reduced synapse number and impaired auditory responses. In contrast, exogenous expression of Mafb in SGNs accelerated afferent synapse development in mice. Further analysis using Gata3 (131320) CKO mice showed that Mafb acted downstream of Gata3 in a transcriptional cascade that guided SGN development and ensured emergence of cell type-specific features critical for the sense of hearing.
Park et al. (2016) observed that at embryonic day 11.5 (E11.5), Mafb +/- mice had hypoplastic abducens nerves, whereas Mafb -/- mice showed severe malformations of the hindbrain and as a result were missing abducens nerves and displayed fusion of the glossopharyngeal and vagus nerves. Using an orbital dissection technique to visualize the developing cranial nerves and extraocular muscles in mouse embryos, Park et al. (2016) observed that by E12.5, the abducens nerve was present in the orbit and contacted the developing lateral rectus (LR) muscle in wildtype embryos. In Mafb +/- embryos, however, a hypoplastic abducens nerve contacted the developing LR muscle, and aberrant branches of the oculomotor nerve began to form in the direction of the LR muscle and retractor bulbi (RB) muscle. In Mafb -/- embryos, the abducens nerve was absent, and an aberrant branch of the oculomotor nerve formed and contacted the developing LR muscle along a trajectory similar to that of the wildtype abducens nerve, whereas other aberrant branches developed and contacted the RB muscle. By E16.5, wildtype embryos had developed the adult configuration of extraocular muscles and cranial nerves, whereas in Mafb +/- embryos, the abducens nerve remained hypoplastic in comparison to wildtype but provided some innervation to the LR muscle, and in Mafb -/- embryos, the abducens nerve was absent and provided no innervation to the LR muscle. In both heterozygous and null embryos, the LR muscle received innervation from aberrant oculomotor nerve branches. Park et al. (2016) concluded that aberrant innervation of the LR muscle by the oculomotor nerve in Duane retraction syndrome-3 (DURS3; 617041) arises as a secondary mechanism due to absent or reduced LR muscle innervation by the abducens nerve.
In a patient with multicentric carpotarsal osteolysis syndrome (MCTO; 166300), Zankl et al. (2012) identified heterozygosity for a 184A-C transversion in the MAFB gene, resulting in a thr62-to-pro (T62P) substitution at a highly conserved residue within the N-terminal transcription activation domain. The mutation was not found in the unaffected parents or in 164 controls.
In a patient with multicentric carpotarsal osteolysis syndrome (MCTO; 166300), Zankl et al. (2012) identified heterozygosity for a 208T-G transversion in the MAFB gene, resulting in a ser70-to-ala (S70A) substitution at a highly conserved residue within the N-terminal transcription activation domain. The mutation was not found in the unaffected parents or in 164 controls.
In 2 unrelated probands with multicentric carpotarsal osteolysis syndrome (MCTO; 166300), Zankl et al. (2012) identified heterozygosity for a 209C-T transition in the MAFB gene, resulting in a ser70-to-leu (S70L) substitution at a highly conserved residue within the N-terminal transcription activation domain. The mutation was not found in the unaffected parents or in 164 controls.
In a 3-year-old patient and an unrelated 7-year-old patient with multicentric carpotarsal osteolysis syndrome (MCTO; 166300), Zankl et al. (2012) identified heterozygosity for a 211C-T transition in the MAFB gene, resulting in a pro71-to-ser (P71S) substitution at a highly conserved residue within the N-terminal transcription activation domain. The mutation was not found in the unaffected parents or in 164 controls. Neither patient had evidence of renal disease as yet, although Zankl et al. (2012) noted that an older affected individual with a different mutation at the same residue (P71L; 608968.0005) had manifested renal disease.
In a patient with multicentric carpotarsal osteolysis syndrome (MCTO; 166300), Zankl et al. (2012) identified heterozygosity for a 212C-T transition in the MAFB gene, resulting in a pro71-to-leu (P71L) substitution at a highly conserved residue within the N-terminal transcription activation domain. The mutation was not found in the unaffected parents or in 164 controls.
In affected individuals from 2 unrelated multigenerational families with multicentric carpotarsal osteolysis syndrome (MCTO; 166300), Zankl et al. (2012) identified heterozygosity for a 161C-T transition in the MAFB gene, resulting in a ser54-to-leu (S54L) substitution at a highly conserved residue within the N-terminal transcription activation domain. The mutation was not found in unaffected family members or in 164 controls. Zankl et al. (2012) noted that affected individuals from these 2 families, many of whom were adults, did not manifest renal disease, with the exception of 1 patient who 'at a very old age' developed renal dysfunction of unknown etiology; the authors therefore concluded that MAFB mutations are also responsible for MCTO in the absence of renal disease.
In 4 affected members of a family (family FA) with Duane retraction syndrome and hearing loss (DURS3; 617041), Park et al. (2016) identified heterozygosity for a 1-bp deletion (c.803delA, NM_005461.4) within the LZ of the MAFB gene, causing a frameshift predicted to result in premature termination codon (Asn268MetfsTer125), with retention of the EHR and BR domains in the mutant protein. Functional analysis by luciferase assay in transfected HEK293T cells showed no activity with the mutant protein alone, and reduced transcriptional activity of wildtype MAFB when coexpressed with the mutant, consistent with a dominant-negative mechanism. Affected members of this family exhibited phenotypic variability, having either type 1 or type 3 DURS, which was unilateral and right-sided in the mother and 2 affected sons, and bilateral in the affected granddaughter. The mother and 1 son also had right-sided deafness, whereas the granddaughter had bilateral deafness; her affected father did not report deafness, but had not undergone formal hearing testing.
In a male patient (family 0819) with bilateral type 1 Duane retraction syndrome (DURS3; 617041), Park et al. (2016) identified heterozygosity for a 1-bp deletion (c.440delG, NM_005461.4) between the N-terminal polyhistidine regions, causing a frameshift predicted to result in a premature termination codon (Gly147AlafsTer78). Functional analysis by luciferase assay in transfected HEK293T cells showed no activity with the mutant protein alone; there was no change in transcriptional activity of wildtype MAFB when coexpressed with the mutant, consistent with a loss-of-function mechanism.
In a father and 2 daughters (family PM) with bilateral Duane retraction syndrome (DURS3; 617041), Park et al. (2016) identified heterozygosity for a 1-bp deletion (c.644delA, NM_005461.4) at the beginning of the EHR domain, causing a frameshift predicted to result in a premature termination codon (Gln215ArgfsTer10). The father and 1 of the affected daughters had type 3 DURS on the right and type 1 DURS on the left, whereas the other daughter had type 3 DURS bilaterally.
In 6 affected members over 2 generations of a family (family N) with Duane retraction syndrome (DURS3; 617041), Park et al. (2016) identified heterozygosity for an approximately 600-kb deletion on chromosome 20, encompassing only the MAFB gene (GRCh37). Affected individuals had unilateral (right-sided) or bilateral DURS, which in 2 of the patients was reported to be type 3.
Artner, I., Blanchi, B., Raum, J. C., Guo, M., Kaneko, T., Cordes, S., Sieweke, M., Stein, R. MafB is required for islet beta cell maturation. Proc. Nat. Acad. Sci. 104: 3853-3858, 2007. [PubMed: 17360442] [Full Text: https://doi.org/10.1073/pnas.0700013104]
Aziz, A., Soucie, E., Sarrazin, S., Sieweke, M. H. MafB/c-Maf deficiency enables self-renewal of differentiated functional macrophages. Science 326: 867-871, 2009. [PubMed: 19892988] [Full Text: https://doi.org/10.1126/science.1176056]
Garzon, R., Pichiorri, F., Palumbo, T., Iuliano, R., Cimmino, A., Aqeilan, R., Volinia, S., Bhatt, D., Alder, H., Marcucci, G., Calin, G. A., Liu, C.-G., Bloomfield, C. D., Andreeff, M., Croce, C. M. MicroRNA fingerprints during human megakaryocytopoiesis. Proc. Nat. Acad. Sci. 103: 5078-5083, 2006. [PubMed: 16549775] [Full Text: https://doi.org/10.1073/pnas.0600587103]
Park, J. G., Tischfield, M. A., Nugent, A. A., Cheng, L., Di Gioia, S. A., Chan, W.-M., Maconachie, G., Bosley, T. M., Summers, C. G., Hunter, D. G., Robson, C. D., Gottlob, I., Engle, E. C. Loss of MAFB function in humans and mice causes Duane syndrome, aberrant extraocular muscle innervation, and inner-ear defects. Am. J. Hum. Genet. 98: 1220-1227, 2016. [PubMed: 27181683] [Full Text: https://doi.org/10.1016/j.ajhg.2016.03.023]
Petersen, H. H., Hilpert, J., Jacobsen, C., Lauwers, A., Roebroek, A. J. M., Willnow, T. E. Low-density lipoprotein receptor-related protein interacts with MafB, a regulator of hindbrain development. FEBS Lett. 565: 23-27, 2004. [PubMed: 15135046] [Full Text: https://doi.org/10.1016/j.febslet.2004.03.069]
Wang, P. W., Eisenbart, J. D., Cordes, S. P., Barsh, G. S., Stoffel, M., Le Beau, M. M. Human KRML (MAFB): cDNA cloning, genomic structure, and evaluation as a candidate tumor suppressor gene in myeloid leukemias. Genomics 59: 275-281, 1999. [PubMed: 10444328] [Full Text: https://doi.org/10.1006/geno.1999.5884]
Yu, W.-M., Appler, J. M., Kim, Y.-H., Nishitani, A. M., Holt, J. R., Goodrich, L. V. A Gata3-Mafb transcriptional network directs post-synaptic differentiation in synapses specialized for hearing. eLife 2: e01341, 2013. [PubMed: 24327562] [Full Text: https://doi.org/10.7554/eLife.01341]
Zankl, A., Duncan, E. L., Leo, P. J., Clark, G. R., Glazov, E. A., Addor, M.-C., Herlin, T., Kim, C. A., Leheup. B. P., McGill, J., McTaggart, S., Mittas, S., Mitchell, A. L., Mortier, G. R., Robertson, S. P., Schroeder, M., Terhal, P., Brown, M. A. Multicentric carpotarsal osteolysis is caused by mutations clustering in the amino-terminal transcriptional activation domain of MAFB. Am. J. Hum. Genet. 90: 494-501, 2012. Note: Erratum: Am. J. Hum. Genet. 94: 643 only, 2014. [PubMed: 22387013] [Full Text: https://doi.org/10.1016/j.ajhg.2012.01.003]