Alternative titles; symbols
HGNC Approved Gene Symbol: MAB21L1
Cytogenetic location: 13q13.3 Genomic coordinates (GRCh38): 13:35,473,789-35,476,689 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 13q13.3 | Cerebellar, ocular, craniofacial, and genital syndrome | 618479 | Autosomal recessive | 3 |
Margolis et al. (1996) cloned the MAB21L1 gene from a retinal cDNA library. The gene encodes a 359-amino acid protein that is homologous to the C. elegans cell fate-determining protein mab21 (56% identical and 81% conserved amino acids). Northern blot analysis revealed that MAB21L1 is expressed in a number of tissues, with highest expression in brain, particularly in the cerebellum.
Using in situ hybridization, Mariani et al. (1998) showed that onset of Mab21 expression occurred at 8.5 days postcoitum in mouse embryos. At midgestation, Mab21 showed highest expression in rhombencephalon, cerebellum, midbrain, and prospective neural retina, and it remained expressed in postnatal cerebellum and eye.
Mariani et al. (1999) cloned and characterized the human MAB21L2 gene (604357) and the murine Mab21l1 and Mab21l2 genes. The C. elegans mab21 gene participates in the formation of sensory organs in the male nematode tail and is essential for other developmental functions elsewhere in the embryo. The 2 mammalian genes, which encode 41-kD nuclear basic proteins, are expressed in partially overlapping territories in the embryonic brain, eye, and limbs, as well as in neural crest derivatives. Based on genetic data implicating mab21 as a downstream target of transforming growth factor-beta (TGFB1; 190180) signaling, together with the distribution of Mab21 transcripts in the mouse embryo, Mariani et al. (1999) proposed that these novel genes are relevant factors in various aspects of vertebrate neural development.
By use of a chromosomal-rodent hybrid panel, Margolis et al. (1996) mapped the MAB21L1 gene to chromosome 13. Using the polymorphic CAG repeat within MAB21L1, they performed linkage analysis in 4 CEPH families to localize the gene to the region of D13S220 (maximum lod = 18.96 at theta = 0.0). By radiation hybrid mapping, they further refined the location to 13q13, telomeric to D13S220.
Cerebellar, Ocular, Craniofacial, and Genital Syndrome
In an 8-year-old Algerian boy with cerebellar malformation, ocular anomalies, facial dysmorphism, and scrotal agenesis (COFG; 618479), Bruel et al. (2017) identified homozygosity for a 1-bp duplication in the MAB21L1 gene (601280.0001) that was present in heterozygosity in his unaffected first-cousin parents and not carried by his 2 unaffected sisters.
Rad et al. (2019) reported 10 patients from 5 unrelated families with a strikingly similar syndromic labioscrotal aplasia phenotype, all of whom were homozygous for mutations in the MAB21L1 gene (see, e.g., 601280.0002-601280.0005) that segregated fully with disease in their respective families.
Associations Pending Confirmation
Margolis et al. (1996) found that a CAG trinucleotide repeat occurs in the 5-prime untranslated region of MAB21L1. This repeat is highly polymorphic, with alleles ranging from 6 to 31 repeats. Margolis et al. (1996) reported that an individual with an idiopathic movement disorder and affective disorder had an MAB21L1 allele that contained 46 repeats.
Potter (1997) analyzed 928 chromosomes from controls and patients with a variety of neurologic diseases. He found a normal CAG repeat size range of 9 to 29 repeats. One individual with developmental delay and mental retardation had 50 repeats; however, 3 other family members with alleles of similar size were apparently normal. Analysis of other family members showed meiotic stability for repeats of normal length and meiotic instability for alleles with 45 or more repeats.
Margolis et al. (1999) reported a second pedigree with an expanded and unstably transmitted MAB21L1 CAG repeat. One individual from this pedigree was included in the report of Margolis et al. (1996). The expansion size ranged up to 51 repeats. The repeat length tended to increase in subsequent generations, but the expanded allele was not associated with a phenotypic abnormality. The pedigree, however, was complex, with a number of individuals affected with neurologic and psychiatric disorders. Repeat length did not influence the level of MAB21L1 protein in lymphoblasts from 2 family members with an expanded MAB21L1 repeat. Margolis et al. (1999) hypothesized that the CAG repeat in MAB21L1 may behave as a premutation, and that longer expansions may be associated with a clinical phenotype.
Yamada et al. (2003) found that Mab21l1 -/- mice were born at mendelian ratios and that Mab21l1 deletion did not affect survival. Most male Mab21l1 -/- mice were sterile, but they could reproduce by in vitro fertilization. Morphologic and histologic analyses showed that adult Mab21l1 -/- mice had eye and preputial gland defects. Mab21l1 was required for formation of normal lens, and loss of Mab21l1 altered expression of crystallin genes (see 123580) and retinal differentiation genes. In chimeric embryos composed of wildtype and Mab21l1 -/- cells, all Mab21l1 -/- cells were excluded from lens, indicating that Mab21l1 protein acts in a cell-autonomous manner during lens formation. Further analysis demonstrated that Mab21l1 was essential for lens placode cell proliferation and for protection against apoptosis. Loss of Mab21l1 resulted in reduction of Foxe3 (601094) expression in lens placode cells, and expression of Pax6 (607108) was essential for Mab21l1 expression in eye surface ectoderm and optic vesicles.
Nguyen et al. (2017) found that Mab21l1 -/- mice had calvarial ossification characterized by an unclosed calvarial region with impaired growth of fontanelle and parietal bones during postnatal development. Real-time PCR analysis of cultured primary calvarial cells showed that Mab21l1 was upregulated during calvarial osteogenesis in wildtype mice. Loss of Mab21l1 in mice resulted in superior osteogenic potential with faster osteogenesis and faster adipogenesis. Mab21l1 -/- calvarial osteoblasts also showed altered expression of osteoclast markers and inflammatory genes.
In an 8-year-old Algerian boy with cerebellar malformation, ocular anomalies, facial dysmorphism, and scrotal agenesis (COFG; 618479), Bruel et al. (2017) identified homozygosity for a 1-bp duplication (c.735dupG, NM_005584.3), causing a frameshift predicted to result in a premature termination codon (Cys246LeufsTer18). His unaffected first-cousin parents were heterozygous for the mutation, which was not found in his 2 unaffected sisters or in 69 local control exomes.
In 3 sibs from a Turkish family (family 5) with cerebellar, ocular, craniofacial, and genital syndrome (COFG; 618479), originally reported by Silay et al. (2013) and restudied by Kayserili et al. (2016), Rad et al. (2019) identified homozygosity for a c.840C-G transversion (c.840C-G, NM_005584.4) in the MAB21L1 gene, resulting in a tyr280-to-ter (Y280X) substitution. Their unaffected first-cousin parents were heterozygous for the mutation.
In a Turkish man (family 4) with cerebellar, ocular, craniofacial, and genital syndrome (COFG; 618479), originally reported by Kayserili et al. (2016), Rad et al. (2019) identified homozygosity for a 1-bp deletion (c.859delC, NM_005584.4) in the MAB21L1 gene, causing a frameshift predicted to result in a premature termination codon (Arg287GlufsTer14). His unaffected second-cousin parents and an unaffected brother were heterozygous for the mutation.
In 3 sibs and an affected cousin from a multiply consanguineous Persian family (family 1) with cerebellar, ocular, craniofacial, and genital syndrome (COFG; 618479), Rad et al. (2019) identified homozygosity for a 1-bp deletion (c.841delG, NM_005584.4) in the MAB21L1 gene, causing a frameshift predicted to result in a premature termination codon (Glu281AspfsTer20). Both sets of unaffected parents and 3 unaffected sibs were heterozygous for the mutation.
In a 2-year-old Persian boy (family 2) with cerebellar, ocular, craniofacial, and genital syndrome (COFG; 618479), Rad et al. (2019) identified homozygosity for a c.698A-C transversion (c.698A-C, NM_005584.4) in the MAB21L1 gene, resulting in a gln233-to-pro (Q233P) substitution at a conserved residue within an alpha helix. His unaffected parents were heterozygous for the mutation.
Bruel, A.-L., Masurel-Paulet, A., Riviere, J.-B., Duffourd, Y., Lehalle, D., Bensignor, C., Huet, F., Borgnon, J., Roucher, F., Kuentz, P., Deleuze, J.-F., Thauvin-Robinet, C., Faivre, L., Thevenon, J. Autosomal recessive truncating MAB21L1 mutation associated with a syndromic scrotal agenesis. Clin. Genet. 91: 333-338, 2017. [PubMed: 27103078] [Full Text: https://doi.org/10.1111/cge.12794]
Kayserili, H., Altunoglu, U., Yesil, G., Rosti, R. O. Microcephaly, dysmorphic features, corneal dystrophy, hairy nipples, underdeveloped labioscrotal folds, and small cerebellum in four patients. Am. J. Med. Genet. 170A: 1391-1399, 2016. [PubMed: 27075597] [Full Text: https://doi.org/10.1002/ajmg.a.37652]
Margolis, R. L., Stine, O. C., McInnis, M. G., Ranen, N. G., Rubinsztein, D. C., Leggo, J., Brando, L. V. J., Kidwai, A. S., Loev, S. J., Breschel, T. S., Callahan, C., Simpson, S. G., and 12 others. cDNA cloning of a human homologue of the Caenorhabditis elegans cell fate-determining gene mab-21: expression, chromosomal localization and analysis of a highly polymorphic (CAG)n trinucleotide repeat. Hum. Molec. Genet. 5: 607-616, 1996. [PubMed: 8733127] [Full Text: https://doi.org/10.1093/hmg/5.5.607]
Margolis, R. L., Stine, O. C., Ward, C. M., Franz, M. L., Rosenblatt, A., Callahan, C., Sherr, M., Ross, C. A., Potter, N. T. Unstable expansion of the CAG trinucleotide repeat in MAB21L1: report of a second pedigree and effect on protein expression. J. Med. Genet. 36: 62-64, 1999. [PubMed: 9950369]
Mariani, M., Baldessari, D., Francisconi, S., Viggiano, L., Rocchi, M., Zappavigna, V., Malgaretti, N., Consalez, G. G. Two murine and human homologs of mab-21, a cell fate determination gene involved in Caenorhabditis elegans neural development. Hum. Molec. Genet. 8: 2397-2406, 1999. [PubMed: 10556287] [Full Text: https://doi.org/10.1093/hmg/8.13.2397]
Mariani, M., Corradi, A., Baldessari, D., Malgaretti, N., Pozzoli, O., Fesce, R., Martinez, S., Boncinelli, E., Consalez, G. G. Mab21, the mouse homolog of a C. elegans cell-fate specification gene, participates in cerebellar, midbrain and eye development. Mech. Dev. 79: 131-135, 1998. [PubMed: 10349626] [Full Text: https://doi.org/10.1016/s0925-4773(98)00180-4]
Nguyen, D., Yamada, R., Yoshimitsu, N., Oguri, A., Kojima, T., Takahashi, N. Involvement of the Mab21l1 gene in calvarial osteogenesis. Differentiation 98: 70-78, 2017. [PubMed: 29156428] [Full Text: https://doi.org/10.1016/j.diff.2017.11.001]
Potter, N. T. Meiotic instability associated with the CAGR1 trinucleotide repeat at 13q13. J. Med. Genet. 34: 411-413, 1997. [PubMed: 9152839] [Full Text: https://doi.org/10.1136/jmg.34.5.411]
Rad, A., Altunoglu, U., Miller, R., Maroofian, R., James, K. N., Caglayan, A. O., Najafi, M., Stanley, V., Boustany, R.-M., Yesil, G., Sahebzamani, A., Ercan-Sencicek, G., and 9 others. MAB21L1 loss of function causes a syndromic neurodevelopmental disorder with distinctive cerebellar, ocular, craniofacial and genital features (COFG syndrome). J. Med. Genet. 56: 332-339, 2019. [PubMed: 30487245] [Full Text: https://doi.org/10.1136/jmedgenet-2018-105623]
Silay, M. S., Yesil, G., Yildiz, K., Kilincaslan, H., Ozgen, I. T., Armagan, A. Congenital agenesis of scrotum and labia majora in siblings. Urology 81: 421-423, 2013. [PubMed: 23374822] [Full Text: https://doi.org/10.1016/j.urology.2012.10.019]
Yamada, R., Mizutani-Koseki, Y., Hasegawa, T., Osumi, N., Koseki, H., Takahashi, N. Cell-autonomous involvement of Mab21l1 is essential for lens placode development. Development 130: 1759-1770, 2003. [PubMed: 12642482] [Full Text: https://doi.org/10.1242/dev.00399]