Alternative titles; symbols
HGNC Approved Gene Symbol: MAB21L2
Cytogenetic location: 4q31.3 Genomic coordinates (GRCh38) : 4:150,582,151-150,584,693 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4q31.3 | Microphthalmia/coloboma and skeletal dysplasia syndrome | 615877 | Autosomal dominant; Autosomal recessive | 3 |
The C. elegans mab21 cell fate specification gene participates in the formation of sensory organs in the male nematode tail and is essential for other developmental functions elsewhere in the C. elegans embryo. MAB21L1 (601280), a human homolog of the C. elegans mab21 gene, has been cloned and partially characterized. Mariani et al. (1999) cloned and characterized the human MAB21L2 gene and the murine Mab21l1 and Mab21l2 genes, all of which are homologs of the C. elegans mab21 gene. The 2 mammalian genes, which encode 41-kD nuclear basic proteins of 359 amino acids, 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.
Using optical projection tomography in addition to bright-field imaging, Rainger et al. (2014) examined expression of Mab21l2 in mouse embryos at 10.5 days postcoitum and observed strong expression in the rostral and distal regions of the developing neural retina, with no expression immediately adjacent to the closing optic fissure. Expression was also observed in the dorsal and ventral aspects of the developing forelimb bud and in the developing pharyngeal arches, as well as in the midbrain.
Deml et al. (2015) evaluated mab21l2 expression in zebrafish using situ hybridization and observed expression in the presumptive eye field and midbrain at 18 hours postfertilization (hpf). At 24 hpf, mab21l2 expression was seen in the retina, lens, spinal cord, midbrain, and pharyngeal arch region. In 48 to 72 hpf, transcripts could be detected in the germinal zone of the retina that contains multipotent retinal progenitors, in the inner nuclear and ganglion cell layers of the retina, and around the optic fissure in the eye, as well as in the midbrain, hindbrain, developing fins,and branchial arches.
By PCR screening of a YAC library and by FISH, Mariani et al. (1999) mapped the MAB21L2 gene to chromosome 4q31. They mapped the murine Mab21l2 gene to chromosome 3, in a region showing homology of synteny with human 4q31, by haplotype and linkage analysis of a backcross DNA panel.
In 3 independent exome-sequencing projects, Rainger et al. (2014) identified 4 different missense mutations in the MAB21L2 gene in 8 patients from 5 unrelated families with bilateral clinical anophthalmia or microphthalmia and coloboma with or without rhizomelic skeletal dysplasia (MCSKS; 615877). The mutations segregated with the disease in each family and were not found in public databases, including those of the 1000 Genomes Project and the NHLBI Exome Variant Server. In 4 of the families, the mutations were heterozygous and located near each other, involving R51 in 3 families (R51H, 604357.0001; R51C, 604357.0002) and E49 (E49K; 604357.0003) in 1 family; however, 2 brothers born of consanguineous parents were homozygous for an R247Q mutation (604257.0004) for which their unaffected parents were both heterozygous. Rainger et al. (2014) stated that the restricted repertoire of mutations in the monoallelic cases strongly suggested an unusual genetic mechanism beyond simple loss of function; they further noted that the 2 patients with homozygous mutations were the least severely affected. All 4 mutations resulted in complete loss of the single-stranded RNA (ssRNA)-binding activity observed with wildtype MAB21L2, and the 3 heterozygous mutations showed significant stabilization of the protein compared to wildtype or the R247Q mutant. On immunoblot analysis, induction of wildtype MAB21L2 consistently resulted in an approximately 1.5-fold increase in phospho-ERK1 (MAPK3; 601795), and a similar level of induction was observed with the R51H substitution; the combination of protein stabilization and phospho-ERK1 induction suggested that the monoallelic MAB21L2 mutations might be activating mutations.
In a 3-generation family with coloboma, microcornea, cataracts, and skeletal dysplasia, Deml et al. (2015) identified heterozygosity for a missense mutation in the MAB21L2 gene (R51G; 604357.0005) that segregated with disease and was not found in public variant databases.
Deml et al. (2015) generated zebrafish homozygous for frameshift truncating mutations in the mab21l2 gene and observed microphthalmia with small or absent lens in 100% of affected embryos, as well as coloboma and shortened body/curved tail in 76% and 56% of affected fish, respectively. The phenotype was first evident in 24 to 48 hpf embryos and became progressively worse. Zebrafish homozygous for an in-frame mab21l2 deletion showed an abnormal phenotype at 72 hpf, consisting of severe ocular coloboma in all affected embryos and corneal defects in 42%, whereas the lens and eye size appeared to be only mildly affected. Histologic analysis of embryos homozygous for frameshift mutations showed a small degenerative or absent lens, disorganized retina, and irregular cornea. Histologic analysis of embryos homozygous for the in-frame mab21l2 deletion showed severe coloboma, abnormally formed retina and cornea, discontinuous retinal pigment epithelium (RPE), as well as generally normal eye size and lens appearance. Alcian blue staining identified craniofacial defects in some of the embryos from both groups, whereas there were no obvious malformations of the pectoral fin. Deml et al. (2015) noted that homozygosity for the frameshift mutation was uniformly lethal, whereas 13% of embryos homozygous for the in-frame deletion survived to adulthood. Examination of the adult fish showed a severe ocular phenotype, with anophthalmia of 1 eye and microphthalmia of the other. In addition, ocular structures appeared to be highly disorganized with an expanded anterior segment and pigmented cornea. Analysis of apoptosis with TUNEL assays revealed a significant increase in TUNEL staining in the developing retina and lens of embryos homozygous for the frameshift mutation. An increase in TUNEL staining was also observed at later stages of development, and was present to a lesser degree in embryos homozygous for the in-frame deletion.
In affected individuals from a large 3-generation family (family 1463) with microphthalmia and coloboma with or without rhizomelic skeletal dysplasia (MCSKS14; 615877), Rainger et al. (2014) identified heterozygosity for a c.152G-A transition in the MAB21L2 gene (g.151504333G-A; GRCh37), resulting in an arg51-to-his (R51H) substitution at a highly conserved residue. The mutation segregated with disease in the family and was not found in the 1000 Genomes Project or the NHLBI ESP Exome Variant Server databases, or in the Medical Research Council Human Genetics Unit in-house database of variants derived from approximately 2,200 exomes. Fluorometric analysis demonstrated complete loss of ssRNA-binding activity with the R51H mutant, and the mutant protein showed higher stability than wildtype in tetracycline-inducible HEK293 cells. In addition to ocular malformations, the 13-year-old proband exhibited skeletal changes, including bilateral joint contractures of the knees and hips, hypoplastic femoral condyles, and pes planus, as well as wasting of the calf muscles and hypospadias, whereas his uncle and a male cousin, who also carried the R51H mutation, had only ocular findings.
In a 10-year-old Norwegian girl (family 676) and an unrelated 24-year-old man (family 4480) with bilateral clinical anophthalmia, severe bilateral rhizomelia, and contractures of all large joints (MCSKS; 615877), Rainger et al. (2014) identified heterozygosity for a de novo c.151C-T transition in the MAB21L2 gene (g.151504332G-A; GRCh37), resulting in an arg51-to-cys (R51C) substitution at a highly conserved residue. The mutation was not found in their unaffected parents. Fluorometric analysis demonstrated complete loss of ssRNA-binding activity with the R51C mutant, and the mutant protein showed higher stability than wildtype in tetracycline-inducible HEK293 cells. Additional findings in the girl included macrocephaly and precocious puberty at age 7 years, and in the man, hypoplastic femoral condyles; both had moderate intellectual disability, and the girl also exhibited features of autistic spectrum disorder.
In a 39-year-old man (family 131) with bilateral microphthalmia, coloboma, and microcornea as well as minor skeletal dysmorphism (MCSKS; 615877), Rainger et al. (2014) identified heterozygosity for a c.145G-A transition in the MAB21L2 gene (g.151504326G-A; GRCh37), resulting in a glu49-to-lys (E49K) substitution at a highly conserved residue. DNA was unavailable from the patient's unaffected deceased mother, but the mutation was not found in his unaffected father or in the 1000 Genomes Project, the NHLBI Exome Variant Server, or the UK10K variant databases. Fluorometric analysis demonstrated complete loss of ssRNA-binding activity with the E49K mutant, and the mutant protein showed higher stability than wildtype in tetracycline-inducible HEK293 cells. The patient had fairly good vision until 11 years of age, after which he became blind over a period of 2 years. There was no evidence of retinal detachment; no retinal electrophysiology was available. Other features included recurrent dislocations of the patella and soft-tissue syndactyly of fingers 3 and 4 and toes 2 and 3; he also had bilateral undescended testes.
In 2 brothers (family 4468) with bilateral coloboma, 1 of whom also had unilateral microphthalmia (MCSKS; 615877), born of first-cousin parents, Rainger et al. (2014) identified homozygosity for a c.740G-A transition in the MAB21L2 gene (g.151504921G-A; GRCh37), resulting in an arg247-to-gln (R247Q) substitution at a highly conserved residue. Their first-cousin unaffected parents, who had normal vision and no evidence of an asymptomatic structural eye malformation on examination, were heterozygous for the mutation, which was not found in the 1000 Genomes Project, the NHLBI Exome Variant Server, or the Atherosclerosis Risk in Communities Study databases, or in an in-house exome variant database from approximately 2,500 individuals. Fluorometric analysis demonstrated complete loss of ssRNA-binding activity with the R247Q mutant. Both brothers, aged 3 and 5 years, exhibited facial dysmorphism, including prominent forehead, periorbital fullness, long eyelashes, epicanthus, and long and prominent philtrum, and both had unilateral strabismus. The younger brother also had mild shortening of the long bones with decreased tubulation, but the older brother exhibited no skeletal changes.
In 5 affected members of a family with coloboma, microcornea, cataracts, and skeletal dysplasia (MCSKS; 615877), Deml et al. (2015) identified heterozygosity for a c.151C-G transversion in the MAB21L2 gene, resulting in an arg51-to-gly (R51G) substitution at a conserved residue. The mutation segregated with disease in the family and was not found in the Exome Variant Server, dbSNP, or 1000 Genomes Project databases. The proband's unaffected mother showed a low 'G' peak at c.151 in addition to the wildtype 'C' upon sequencing, suggesting low-level mosaicism for the mutation. Functional analysis in HLEB3 cells showed that the R51G mutant was present at levels approximately 32% of those of wildtype MAB21L2, and protein stability assays showed a more rapid decrease in the amount of mutant compared to the wildtype protein at all time points examined, suggesting reduced stability of the R51G mutant. In addition, wildtype MAB21L2 mRNA showed efficient rescue of ocular anomalies in zebrafish embryos homozygous for a mab21l2 frameshift mutation (see ANIMAL MODEL), whereas there was an absence of robust rescue by mutant mRNA (68% versus 14%). No dominant-negative effect for the R51G mutant allele was observed.
Deml, B., Kariminejad, A., Borujerdi, R. H. R., Muheisen, S., Reis, L. M., Semina, E. V. Mutations in MAB21L2 result in ocular coloboma, microcornea and cataracts. PLoS Genet. 11: e1005002, 2015. [PubMed: 25719200] [Full Text: https://doi.org/10.1371/journal.pgen.1005002]
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]
Rainger, J., Pehlivan, D., Johansson, S., Bengani, H., Sanchez-Pulido, L., Williamson, K. A., Ture, M., Barker, H., Rosendahl, K., Spranger, J., Horn, D., Meynert, A., and 25 others. Monoallelic and biallelic mutations in MAB21L2 cause a spectrum of major eye malformations. Am. J. Hum. Genet. 94: 915-923, 2014. [PubMed: 24906020] [Full Text: https://doi.org/10.1016/j.ajhg.2014.05.005]