Alternative titles; symbols
HGNC Approved Gene Symbol: LBX1
Cytogenetic location: 10q24.32 Genomic coordinates (GRCh38) : 10:101,226,994-101,229,463 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q24.32 | ?Central hypoventilation syndrome, congenital, 3 | 619483 | Autosomal recessive | 3 |
The LBX1 gene encodes a homeodomain transcription factor that plays a role in neuron-specific gene expression that influences neuronal fate during development (summary by Hernandez-Miranda et al., 2018).
Jagla et al. (1995) cloned 2 novel homeobox genes that are the mouse and human homologs of the Drosophila ladybird late gene. The authors designated the mammalian genes Lbx1/LBX1 (ladybird-like homeobox). These genes are highly related not only within the coding region but also in the 5-prime and 3-prime untranslated regions. Both the human and mouse LBX1 genes display structural similarities with HOX transcription units: both contain 2 exons separated by a short intron, the homeobox being located toward the 5-prime extremity of the second exon. The human LBX1 gene encodes a 280-amino acid protein that shows 94% identity to the mouse protein. Several amino acid residues inside and around the homeodomain have been conserved between the mammalian LBX genes and their Drosophila counterparts.
By RT-PCR and in situ hybridization analysis, Jagla et al. (1995) determined that the mouse Lbx1 gene is specifically expressed during embryogenesis, with expression restricted to the developing central nervous system and muscles. Mennerich et al. (1998) characterized Lbx1 homeobox genes in chicken and mice and found them to be expressed in migrating limb muscle precursor cells in both species. Analysis of splotch mutant mice showed that Lbx1 and Met (164860) are affected differently by the lack of Pax3 (604255), which is mutant in splotch mice. Limb buds from these mice were devoid of Lbx1 transcripts while expressing Met at a low level. Mennerich et al. (1998) concluded that Pax3 is necessary but not sufficient for Lbx1 expression in myogenic precursor cells of the limb.
Schafer and Braun (1999) showed that Lbx1h determines migratory routes of muscle precursor cells in a cell-autonomous manner, thereby leading to the formation of distinct limb muscle patterns. Inactivation of Lbx1h, which is specifically expressed in migrating muscle precursor cells, led to a lack of extensor muscles in forelimbs and an absence of muscles in hindlimbs. The defect was caused by the failure of all muscle precursor cells of hindlimbs and of precursor cells of extensor muscles of forelimbs to migrate to their corresponding muscle anlagen. The results demonstrated that Lbx1h is a key regulator of muscle precursor cell migration and is required for the acquisition of dorsal identities of forelimb muscles.
To examine the function of Lbx1 in muscle development, Gross et al. (2000) and Brohmann et al. (2000) independently used homologous recombination to inactivate the Lbx1 gene in mice. Mice lacking Lbx1 exhibited an extensive loss of limb muscles, although some forelimb and hindlimb muscles were still present. The pattern of muscle loss led Gross et al. (2000) to hypothesize that LBX1 regulates responsiveness to a lateral migration signal that emanates from the developing limb. Similarly, Brohmann et al. (2000) concluded that Lbx1 controls the expression of genes that are essential for the recognition or interpretation of cues that guide migrating muscle precursors and maintain their migratory potential.
In independent studies, Muller et al. (2002) and Gross et al. (2002) used sets of molecular markers for detailed immunohistologic analysis in mouse embryos to group neurons in the dorsal spinal cord into 2 major neuronal classes based on Lbx1 expression. Muller et al. (2002) called neurons without Lbx1 expression class A, and those with Lbx1 expression class B. They observed that misexpression of Lbx1 in the chick spinal cord blocked the differentiation of class A neurons; conversely, class B neurons assumed the identity of class A neurons in Lbx1 mutant mice. Similarly, Gross et al. (2002) found that cell types that arose in the ventral alar plate acquired more dorsal identities in mice lacking Lbx1. Both Muller et al. (2002) and Gross et al. (2002) concluded that Lbx1 is important for specification of neurons in the dorsal spinal cord.
In mice, Huang et al. (2019) showed that spinal neurons marked by coexpression of Tac1 (162320) and Lbx1 drive coping responses associated with pain. Ablation of these spinal neurons led to the loss of both persistent licking and conditioned aversion evoked by stimuli (including skin pinching and burn injury) that, in humans, produce sustained pain, without affecting any of the reflexive defensive reactions that were tested. This selective indifference to sustained pain resembles the phenotype seen in humans with lesions of medial thalamic nuclei. Consistently, spinal Tac1-lineage neurons are connected to medial thalamic nuclei by direct projections and via indirect routes through the superior lateral parabrachial nuclei. Furthermore, the anatomic and functional segregation observed at the spinal level also applies to primary sensory neurons. for example, in response to noxious mechanical stimuli, Mrgprd (607231)- and Trpv1 (602076)-positive nociceptors are required to elicit reflexive and coping responses, respectively. Huang et al. (2019) concluded that their study revealed a fundamental subdivision within the cutaneous somatosensory system, and challenged the validity of using reflexive defensive responses to measure sustained pain.
By in situ hybridization on metaphase spreads of mice and human lymphocytes, Jagla et al. (1995) mapped the mouse Lbx1 gene to chromosome 19 (region D) and the human LBX1 gene to the syntenic 10q24 region, known as a breakpoint region in translocations t(7;10) and t(10;14) involved in T-cell leukemias. Thus, LBX1 and the protooncogene HOX11 (186770) map to the same region, as do their Drosophila homologs.
In 2 brothers, born of consanguineous parents, with congenital central hypoventilation syndrome-3 (CCHS3; 619483), who were negative for PHOX2B (603851) mutations, Hernandez-Miranda et al. (2018) identified a homozygous frameshift mutation in exon 2 of the LBX1 gene (604255.0001). The mutation, which was found by candidate gene sequencing, segregated with the disorder in the family. It was not present in the ExAC or 1000 Genomes Project databases. The mutation resulted in a frameshift and premature termination that altered the C terminus of the protein but did not affect the homeodomain. Studies of patient cells were not performed. In vitro studies in cells derived from mutant mice with an analogous frameshift mutation (see ANIMAL MODEL) showed that the mutant protein had mildly altered binding affinity to certain targets compared to wildtype, but more importantly, failed to cooperate productively with its partner PHOX2B, causing impaired development of a subpopulation of dB2 neurons in the retrotrapezoid nucleus (RTN) essential for respiratory control. The mutant protein functioned normally for the development of somatosensory neurons and limb muscles, suggesting that the mutation has a specific detrimental effect.
Pagliardini et al. (2008) found that Lbx1 mutant mice displayed both abnormal limb morphology and profound apnea. In vitro analysis of brainstem-spinal cord preparations showed that Lbx1 mutant had normal inception of respiratory rhythmogenesis at embryonic day-15 (E15). However, the typical age-dependent increase in respiratory frequency was not observed in Lbx1 mutant mice from E15 to postnatal day-0. The slow respiratory rhythms in mutant mice were increased to wildtype frequencies by treatment with excitatory neuromodulators at E18.5, suggesting that respiratory rhythm generation within the pre-Botzinger complex (preBotC) was similar to wildtype when provided with the necessary excitatory conditioning neurochemical drive. Anatomic analysis of respiratory nuclei showed that the gross structure of the preBotC was normal in Lbx1 mutant mice, although there were major defects in neuronal populations that provide important modulatory drive to the preBotC, including the retrotrapezoid nucleus, catecholaminergic brainstem nuclei, nucleus of the solitary tract, and populations of inhibitory neurons in the ventrolateral and dorsomedial medullary nuclei. Further analysis showed that these defects were caused by abnormalities of neuronal specification early in development or subsequent neuronal migration.
Hernandez-Miranda et al. (2018) found that homozygous mice carrying a frameshift mutation in the Lbx1 gene, which was analogous to the mutation identified in patients with CCHS3 (604255.0001), displayed cyanosis and died within hours of birth due to shallow breathing, long apneas, and hypoventilation. These findings were associated with abnormal migration and function of a subpopulation of dB2 neurons that form the RTN in the ventral hindbrain and are central for the hypercapnic reflex important for breathing.
In 2 brothers, born of consanguineous parents, with congenital central hypoventilation syndrome-3 (CCHS3; 619483), who were negative for PHOX2B (603851) mutations, Hernandez-Miranda et al. (2018) identified a homozygous frameshift mutation in exon 2 of the LBX1 gene. The mutation, which was found by candidate gene sequencing, segregated with the disorder in the family. It was not present in the ExAC or 1000 Genomes Project databases. The mutation resulted in premature termination that altered the C terminus of the protein but did not affect the homeodomain. Studies of patient cells were not performed. Mundlos (2021) stated that the mutation in the LBX1 gene was a 1-bp deletion (c.697delT, ENST00000370193.4), resulting in a frameshift (Val236fs).
Brohmann, H., Jagla, K., Birchmeier, C. The role of Lbx1 in migration of muscle precursor cells. Development 127: 437-445, 2000. [PubMed: 10603359] [Full Text: https://doi.org/10.1242/dev.127.2.437]
Gross, M. K., Dottori, M., Goulding, M. Lbx1 specifies somatosensory association interneurons in the dorsal spinal cord. Neuron 34: 535-549, 2002. [PubMed: 12062038] [Full Text: https://doi.org/10.1016/s0896-6273(02)00690-6]
Gross, M. K., Moran-Rivard, L., Velasquez, T., Nakatsu, M. N., Jagla, K., Goulding, M. Lbx1 is required for muscle precursor migration along a lateral pathway into the limb. Development 127: 413-424, 2000. [PubMed: 10603357] [Full Text: https://doi.org/10.1242/dev.127.2.413]
Hernandez-Miranda, L. R., Ibrahim, D. M., Ruffault, P. L., Larrosa, M., Balueva, K., Muller, T., de Weerd, W., Stolte-Dijkstra, I., Hostra, R. M. W., Brunet, J.-F., Fortin, G., Mundlos, S., Birchmeier, C. Mutation in LBX1/Lbx1 precludes transcription factor cooperativity and causes congenital hypoventilation in humans and mice. Proc. Nat. Acad. Sci. 115: 13021-13026, 2018. [PubMed: 30487221] [Full Text: https://doi.org/10.1073/pnas.1813520115]
Huang, T., Lin, S.-H., Malewicz, N. M., Zhang, Y., Zhang, Y., Goulding, M., LaMotte, R. H., Ma, Q. Identifying the pathways required for coping behaviours associated with sustained pain. Nature 565: 86-90, 2019. [PubMed: 30532001] [Full Text: https://doi.org/10.1038/s41586-018-0793-8]
Jagla, K., Dolle, P., Mattei, M.-G., Jagla, T., Schuhbaur, B., Dretzen, G., Bellard, F., Bellard, M. Mouse Lbx1 and human LBX1 define a novel mammalian homeobox gene family related to the Drosophila lady bird genes. Mech. Dev. 53: 345-356, 1995. [PubMed: 8645601] [Full Text: https://doi.org/10.1016/0925-4773(95)00450-5]
Mennerich, D., Schafer, K., Braun, T. Pax-3 is necessary but not sufficient for lbx1 expression in myogenic precursor cells of the limb. Mech. Dev. 73: 147-158, 1998. [PubMed: 9622616] [Full Text: https://doi.org/10.1016/s0925-4773(98)00046-x]
Muller, T., Brohmann, H., Pierani, A., Heppenstall, P. A., Lewin, G. R., Jessell, T. M., Birchmeier, C. The homeodomain factor Lbx1 distinguishes two major programs of neuronal differentiation in the dorsal spinal cord. Neuron 34: 551-562, 2002. [PubMed: 12062039] [Full Text: https://doi.org/10.1016/s0896-6273(02)00689-x]
Mundlos, S. Personal Communication. Berlin, Germany 9/17/2021.
Pagliardini, S., Ren, J., Gray, P. A., VanDunk, C., Gross, M., Goulding, M., Greer, J. J. Central respiratory rhythmogenesis is abnormal in Lbx1-deficient mice. J. Neurosci. 28: 11030-11041, 2008. [PubMed: 18945911] [Full Text: https://doi.org/10.1523/JNEUROSCI.1648-08.2008]
Schafer, K., Braun, T. Early specification of limb muscle precursor cells by the homeobox gene Lbx1h. Nature Genet. 23: 213-216, 1999. [PubMed: 10508520] [Full Text: https://doi.org/10.1038/13843]