Alternative titles; symbols
HGNC Approved Gene Symbol: LMX1A
Cytogenetic location: 1q23.3 Genomic coordinates (GRCh38) : 1:165,201,867-165,356,715 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q23.3 | Deafness, autosomal dominant 7 | 601412 | Autosomal dominant | 3 |
The LMX1A gene encodes a transcription factor that plays an important role in various developmental processes, including neural progenitor specification and dopamine neurogenesis (summary by Wesdorp et al., 2018 and Schrauwen et al., 2018).
German et al. (1994) isolated human genomic clones for the LMX1 and CDX3 (600297) genes from a human genomic library by cross-hybridization with cDNA clones encoding Syrian hamster proteins. The identities of the clones were confirmed by DNA sequencing.
Using in situ hybridization, Steffes et al. (2012) detected Lmx1a transcripts in otic vesicle and endolymphatic sac of developing inner ear of mouse embryos at embryonic day 10.5 (E10.5). At E12.5, Lmx1a transcripts were also found in the region of fusion plates that later form the semicircular canals. In tissues forming the labyrinth and the cochlear duct, Lmx1a transcripts were restricted to prospective nonsensory inner ear tissue.
By fluorescence in situ hybridization, German et al. (1994) determined that the LMX1 gene is located on distal chromosome 1q22 or the junction of bands 1q22-q23. Church et al. (1994) identified a locus on chromosome 9 that appears to represent a closely related but distinct gene; see 602575.
Insulin is produced exclusively by the beta cells in the islets of Langerhans in the pancreas. The level and beta-cell specificity of insulin gene expression are regulated by a set of nuclear genes that bind to specific sequences within the promoter of the insulin gene (INS; 176730) and interact with RNA polymerase to activate or repress transcription. LMX1 is a homeodomain protein that binds an A/T-rich sequence in the insulin promoter and stimulates transcription of insulin (German et al., 1994).
Andersson et al. (2006) showed that Lmx1a and Msx1 (142983) were determinants of midbrain dopamine neurons in mouse and chicken embryos. Lmx1a was necessary and sufficient to trigger dopamine cell differentiation, and early activity of Lmx1a induced expression of Msx1, which complemented Lmx1a by inducing expression of Ngn2 (NEUROG2; 606624) and neuronal differentiation. Expression of Lmx1a in embryonic stem cells resulted in robust generation of dopamine neurons with midbrain identity. Andersson et al. (2006) concluded that LMX1A and MSX1 are critical intrinsic dopamine neuron determinants.
Caiazzo et al. (2011) identified a minimal set of 3 transcription factors--Mash1 (100790), Nr4a2 (601828), and Lmx1a--that are able to generate directly functional dopaminergic neurons from mouse and human fibroblasts without reverting to a progenitor cell stage. Induced dopaminergic cells released dopamine and showed spontaneous electrical activity organized in regular spikes consistent with the pacemaker activity featured by brain dopaminergic neurons. The 3 factors were able to elicit dopaminergic neuronal conversion in prenatal and adult fibroblasts from healthy donors and Parkinson disease (168600) patients.
Mann et al. (2017) found that sensory organs and nonsensory cells in mouse and chicken inner ear were derived from a common pool of cells through progressive segregation. This process was regulated by mutually antagonistic Notch signaling and Lmx1a (or its functional ortholog in chicken, Lmx1b) signaling. Notch-mediated lateral induction promoted a prosensory fate, whereas Lmx1a signaling antagonized lateral induction and promoted a nonsensory fate.
In affected members of 2 unrelated Dutch families with autosomal dominant deafness-7 (DFNA7; 601412), Wesdorp et al. (2018) identified heterozygous missense mutations at highly conserved residues in the LMX1A gene (V241L, 600298.0001 and C97S, 600298.0002). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Neither was found in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, and the authors postulated haploinsufficiency as a pathogenetic mechanism. However, Wesdorp et al. (2018) noted that Lmx1a +/- mice have normal hearing (see ANIMAL MODEL and Steffes et al., 2012), which is not supportive of haploinsufficiency as the disease mechanism.
Associations Pending Confirmation
For discussion of a possible association between autosomal recessive deafness and variation in the LMX1A gene, see 600298.0003.
Bergstrom et al. (1999) characterized the phenotype of the recessive 'dreher' (dr) mutant mouse, which was later demonstrated to be caused by mutation in the Lmx1a gene (Millonig et al., 2000). Mice homozygous for the dr allele have ataxic gait, circling behavior, impaired righting reflex, hyperactivity, inner ear defects, deafness, and pigmentation abnormalities. Other features include cerebellar hypoplasia, cerebellar foliation and lamination abnormalities, neocortical disruptions of neuronal migration, underdeveloped Mullerian duct derivatives, and skeletal and skull defects. Bergstrom et al. (1999) mapped the dr locus to mouse chromosome 1 in a region with syntenic homology to human chromosome 1q21-q23.
In the vertebrate central nervous system, a cascade of signals that originates in the ectoderm adjacent to the neural tube is propagated by the roof plate to dorsalize the neural tube. Millonig et al. (2000) reported that the phenotype of a spontaneous neurologic mutant mouse, called 'dreher' (dr), results from a failure of the roof plate to develop. Dorsalization of the neural tube is consequently affected: dorsal interneurons in the spinal cord and granule neurons in the cerebellar cortex are lost, and the dorsal vertebral neural arches fail to form. Millonig et al. (2000) used positional cloning to identify the gene mutant in dreher and found that the Lim homeodomain protein Lmx1a is affected in 3 different alleles of dreher. Lmx1a is expressed in the roof plate along the neuraxis during development of the central nervous system and is required for the development of the roof plate and, in turn, for specification of dorsal cell fates in the central nervous system and developing vertebrae.
Steffes et al. (2012) reported that mice homozygous for either the spontaneous mutanlallemand (mtl) mutation or the spontaneous belly spot and deafness (bsd) mutation had similar phenotypes. Homozygotes exhibited circling, head bobbing, and hyperactivity, and were smaller with short tails and white belly patches compared with wildtype. Mutant mice lacked a Preyer reflex, had severe morphologic defects of inner ear, and were profoundly deaf. Heterozygous mice had normal hearing. Complementation tests suggested that both mtl and bsd were mutant alleles of the Lmx1a gene. The authors identified the mtl mutation as a point mutation in the 3-prime splice site of exon 4 of Lmx1a and the bsd mutation as a genomic deletion including exon 3 of Lmx1a. Quantitative RT-PCR analysis revealed that Lmx1a transcripts in both mtl and bsd mutants were significantly downregulated compared with wildtype.
In 3 affected members of a 3-generation Dutch family (W15-0551) with autosomal dominant deafness-7 (DFNA7; 601412), Wesdorp et al. (2018) identified a heterozygous c.721G-C transversion (c.721G-C, NM_001174069.1) in the LMX1A gene, resulting in a val241-to-leu (V241L) substitution at a conserved residue in the homeodomain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing and linkage analysis, segregated with the disorder in the family. It was not found in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but the authors postulated haploinsufficiency as a pathogenetic mechanism.
In 4 affected members of a 2-generation Dutch family (63136) with autosomal dominant deafness-7 (DFNA7; 601412), Wesdorp et al. (2018) identified a heterozygous c.290G-C transversion (c.290G-C, NM_001174069.1) in the LMX1A gene, resulting in a cys97-to-ser (C97S) substitution at a highly conserved residue in the second LIM domain that binds zinc atoms and is essential for DNA binding. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing and linkage analysis, segregated with the disorder in the family. It was not found in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but the authors postulated haploinsufficiency as a pathogenetic mechanism.
This variant is classified as a variant of unknown significance because its contribution to an autosomal recessive sensorineural deafness has not been confirmed.
In 2 brothers, born of consanguineous Pakistani parents (family 4755), with early-onset profound sensorineural hearing loss, Schrauwen et al. (2018) identified a homozygous c.1106T-C transition (c.1106T-C, NM_001174069) in the LMX1A gene, resulting in an ile369-to-thr (I369T) substitution in the conserved C-terminal region. The variant, which was found by a combination of homozygosity mapping and exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was found at a low frequency (1.8 x 10(-5)) in only heterozygous state in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but the authors postulated that I369T is a hypomorphic allele that may compromise LMX1A binding to DNA. The patients presented with congenital prelingual severe to profound hearing loss without vestibular disturbances. The mother was not available for detailed testing, but did not report any hearing loss. The father developed mild late-onset unilateral hearing impairment that was possibly associated with antibiotic intake.
Andersson, E., Tryggvason, U., Deng, Q., Friling, S., Alekseenko, Z., Robert, B., Perlmann, T., Ericson, J. Identification of intrinsic determinants of midbrain dopamine neurons. Cell 124: 393-405, 2006. [PubMed: 16439212] [Full Text: https://doi.org/10.1016/j.cell.2005.10.037]
Bergstrom, D. E., Gagnon, L. H., Eicher, E. M. Genetic and physical mapping of the Dreher locus on mouse chromosome 1. Genomics 59: 291-299, 1999. [PubMed: 10444330] [Full Text: https://doi.org/10.1006/geno.1999.5873]
Caiazzo, M., Dell'Anno, M. T., Dvoretskova, E., Lazarevic, D., Taverna, S., Leo, D., Sotnikova, T. D., Menegon, A., Roncaglia, P., Colciago, G., Russo, G., Carninci, P., Pezzoli, G., Gainetdinov, R. R., Gustincich, S., Dityatev, A., Broccoli, V. Direct generation of functional dopaminergic neurons from mouse and human fibroblasts. Nature 476: 224-227, 2011. [PubMed: 21725324] [Full Text: https://doi.org/10.1038/nature10284]
Church, D. M., Stotler, C. J., Rutter, J. L., Murrell, J. R., Trofatter, J. A., Buckler, A. J. Isolation of genes from complex sources of mammalian genomic DNA using exon amplification. Nature Genet. 6: 98-105, 1994. [PubMed: 8136842] [Full Text: https://doi.org/10.1038/ng0194-98]
German, M. S., Wang, J., Fernald, A. A., Espinosa, R., III, Le Beau, M. M., Bell, G. I. Localization of the genes encoding two transcription factors, LMX1 and CDX3, regulating insulin gene expression to human chromosomes 1 and 13. Genomics 24: 403-404, 1994. [PubMed: 7698771] [Full Text: https://doi.org/10.1006/geno.1994.1639]
Mann, Z. F., Galvez, H., Pedreno, D., Chen, Z., Chrysostomou, E., Zak, M., Kang, M., Canden, E., Daudet, N. Shaping of inner ear sensory organs through antagonistic interactions between Notch signalling and Lmx1a. elife 6: e33323, 2017. Note: Electronic Article. [PubMed: 29199954] [Full Text: https://doi.org/10.7554/eLife.33323]
Millonig, J. H., Millen, K. J., Hatten, M. E. The mouse Dreher gene Lmx1a controls formation of the roof plate in the vertebrate CNS. Nature 403: 764-769, 2000. [PubMed: 10693804] [Full Text: https://doi.org/10.1038/35001573]
Schrauwen, I., Chakchouk, I., Liaqat, K., Jan, A., Nasir, A., Hussain, S., Nickerson, D. A., Bamshad, M. J., Ullah, A., Ahmad, W., Leal, S. M. A variant in LMX1A causes autosomal recessive severe-to-profound hearing impairment. Hum. Genet. 137: 471-478, 2018. [PubMed: 29971487] [Full Text: https://doi.org/10.1007/s00439-018-1899-7]
Steffes, G., Lorente-Canovas, B., Pearson, S., Brooker, R. H., Spiden, S., Kiernan, A. E., Guenet, J. L., Steel, K. P. Mutanlallemand (mtl) and belly spot and deafness (bsd) are two new mutations of Lmx1a causing severe cochlear and vestibular defects. PLoS One 7: e51065, 2012. Note: Electronic Article. [PubMed: 23226461] [Full Text: https://doi.org/10.1371/journal.pone.0051065]
Wesdorp, M., de Koning Gans, P. A. M., Schraders, M., Oostrik, J., Huynen, M. A., Venselaar, H., Beynon, A. J., van Gaalen, J., Piai, V., Voermans, N., van Rossum, M. M., Hartel, B. P., and 14 others. Heterozygous missense variants of LMX1A lead to nonsyndromic hearing impairment and vestibular dysfunction. Hum. Genet. 137: 389-400, 2018. [PubMed: 29754270] [Full Text: https://doi.org/10.1007/s00439-018-1880-5]