Alternative titles; symbols
HGNC Approved Gene Symbol: CLDN11
Cytogenetic location: 3q26.2 Genomic coordinates (GRCh38): 3:170,418,868-170,434,691 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3q26.2 | Leukodystrophy, hypomyelinating, 22 | 619328 | Autosomal dominant | 3 |
The CLDN11 gene encodes a member of the claudin tight junction family. It plays a critical structural role in the radial component of the myelin sheath, where it acts as a diffusion barrier. It is the third most frequent protein identified in central nervous system (CNS) myelin at 7%, after myelin proteolipid protein (PLP1; 300401) and myelin basic protein (MBP; 159430), which represent 40 to 60% (summary by Riedhammer et al., 2021).
Bronstein et al. (1996) isolated a novel oligodendrocyte-specific protein in the mouse. The predicted amino acid sequence and structure of the gene product suggested that the protein, which they symbolized Osp, is the CNS homolog of peripheral myelin protein-22 (601097).
Bronstein et al. (1996) mapped the mouse Osp gene to the proximal region of chromosome 3 using 2 sets of multilocus crosses. They mapped the human OSP gene to chromosome 3 using Southern blot analysis of human/rodent somatic cell hybrids. Fine mapping to human 3q26.2-q26.3 was achieved by fluorescence in situ hybridization. Bronstein et al. (1996) stated that no inherited neurologic disorders had been mapped to that region of human chromosome 3.
Gow et al. (1999) found that Cldn11-null mice exhibited both neurologic and reproductive deficits, including slowed CNS nerve conduction, conspicuous hindlimb weakness, and male sterility. Freeze fracture revealed that tight junction intramembranous strands were absent in CNS myelin and between Sertoli cells of mutant mice. These results demonstrated that OSP is the mediator of parallel-array tight junction strands and distinguished this protein from other intrinsic membrane proteins in tight junctions. In addition, the results provided direct evidence of the pivotal role of the claudin family in generating the paracellular physical barrier of tight junctions necessary for spermatogenesis and normal CNS function.
Smith and Braun (2012) used confocal microscopy to visualize Sertoli cell tight junction components during germ cell cyst migration across the Sertoli cell tight junctions. Cysts become enclosed within a network of transient compartments fully bounded by old and new tight junctions. Dissolution of the old tight junctions releases the germ cells into the adluminal compartment, thus completing transit across the blood-testis barrier. Claudin-3 (602910), a tight junction protein, is transiently incorporated into new tight junctions and then replaced by claudin-11.
In 3 unrelated children with hypomyelinating leukodystrophy-22 (HLD22; 619328), Riedhammer et al. (2021) identified de novo heterozygous mutations in the CLDN11 gene (601326.0001 and 601326.0002). Both mutations, which occurred at the same nucleotide, resulted in a stop-loss, thus extending the protein by 39 residues after the termination codon. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, were absent from public databases, including gnomAD. Analysis of cells from 1 patient showed that CLDN11 transcript levels were similar to those of controls, suggesting that the mutant transcript escapes nonsense-mediated mRNA decay and likely produces an extended protein. Functional studies of the variants were not performed, but molecular modeling predicted that the added residues would add a domain with an alpha helix to the cytoplasmic tail of the protein that would not be incorporated into the cell membrane. This change was predicted to alter protein-protein interactions.
Gow et al. (1999) found that Cldn11-null mice exhibited both neurologic and reproductive deficits, including slowed CNS nerve conduction, conspicuous hindlimb weakness, and male sterility. Freeze fracture revealed that tight junction intramembranous strands were absent in CNS myelin and between Sertoli cells of mutant mice. These results demonstrated that OSP is the mediator of parallel-array tight junction strands and distinguished this protein from other intrinsic membrane proteins in tight junctions.
Maheras et al. (2018) found that transgenic expression of Cldn11 rescued deafness and male infertility in global Cldn11 -/- mice. However, transgenic Cldn11 was not expressed by oligodendrocytes in the CNS of Cldn11 -/- mice. Consequently, transgene expression neither altered CNS myelin properties in Cldn11 -/- mice nor rescued brain-associated phenotypes. Further analysis of Cldn11 -/- mice expressing transgenic Cldn11 revealed 2 behavioral endophenotypes: perturbed auditory processing and reduced anxiety/avoidance.
In 2 unrelated children (patients 1 and 3) with hypomyelinating leukodystrophy-22 (HLD22; 619328), Riedhammer et al. (2021) identified a de novo heterozygous c.622T-C transition (c.622T-C, NM_005602.5) in the CLDN11 gene, resulting in a stop-loss with abnormal extension of the protein by 39 residues beyond the termination codon (Ter208GlnExtTer39). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was absent from public databases, including gnomAD. Analysis of cells from patient 3 showed that CLDN11 transcript levels were similar to controls. Functional studies of the variant were not performed, but molecular modeling predicted that the added residues would add a domain with an alpha helix to the cytoplasmic tail of the protein that would not be incorporated into the cell membrane.
In an 8-year-old Polish boy (patient 2) with hypomyelinating leukodystrophy-22 (HLD22; 619328), Riedhammer et al. (2021) identified a de novo heterozygous c.622T-G transversion (c.622T-G, NM_005602.5) in the CLDN11 gene, resulting in a stop-loss with abnormal extension of the protein by 39 residues beyond the termination codon (Ter208GlnExtTer39). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was absent from public databases, including gnomAD. Functional studies of the variant and studies of patient cells were not performed.
Bronstein, J. M., Kozak, C. A., Chen, X.-N., Wu, S., Danciger, M., Korenberg, J. R., Farber, D. B. Chromosomal localization of murine and human oligodendrocyte-specific protein genes. Genomics 34: 255-257, 1996. [PubMed: 8661061] [Full Text: https://doi.org/10.1006/geno.1996.0278]
Gow, A., Southwood, C. M., Li, J. S., Pariali, M., Riordan, G. P., Brodie, S. E., Danias, J., Bronstein, J. M., Kachar, B., Lazzarini, R. A. CNS myelin and Sertoli cell tight junction strands are absent in Osp/claudin-11 null mice. Cell 99: 649-659, 1999. [PubMed: 10612400] [Full Text: https://doi.org/10.1016/s0092-8674(00)81553-6]
Maheras, K. J., Peppi, M., Ghoddoussi, F., Galloway, M. P., Perrine, S. A., Gow, A. Absence of Claudin 11 in CNS myelin perturbs behavior and neurotransmitter levels in mice. Sci. Rep. 8: 3798, 2018. [PubMed: 29491447] [Full Text: https://doi.org/10.1038/s41598-018-22047-9]
Riedhammer, K. M., Stockler, S., Ploski, R., Wenzel, M., Adis-Dutschmann, B., Ahting, U., Alhaddad, B., Blaschek, A., Haack, T. B., Kopajtich, R., Lee, J., Murcia Pienkowski, V., Pollak, A., Szymanska, K., Tarailo-Graovac, M., van der Lee, R., van Karnebeek, C. D., Meitinger, T., Krageloh-Mann, I., Vill, K. De novo stop-loss variants in CLDN11 cause hypomyelinating leukodystrophy. Brain 144: 411-419, 2021. Note: Erratum: Brain: awab034, 2021. [PubMed: 33313762] [Full Text: https://doi.org/10.1093/brain/awaa410]
Smith, B. E., Braun, R. E. Germ cell migration across Sertoli cell tight junctions. Science 338: 798-802, 2012. [PubMed: 22997133] [Full Text: https://doi.org/10.1126/science.1219969]