Alternative titles; symbols
HGNC Approved Gene Symbol: NRCAM
Cytogenetic location: 7q31.1 Genomic coordinates (GRCh38): 7:108,147,649-108,456,720 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7q31.1 | Neurodevelopmental disorder with neuromuscular and skeletal abnormalities | 619833 | Autosomal recessive | 3 |
The cell adhesion molecules (CAMs) are a subset of the immunoglobin (Ig) superfamily found in the nervous systems of both vertebrates and invertebrates. They are usually surface membrane proteins with multiple Ig domains at their N termini followed by several fibronectin type III repeats and either a transmembrane intracellular domain or a glycophosphatidylinositol-linked membrane anchor at the C terminus (Lane et al., 1996). These proteins are predominantly expressed along axonal pathways, such as the corpus callosum, corticospinal tracts, and optic nerves, where they play a role in functions critical for nervous system development (summary by Kurolap et al., 2022).
The chicken Bravo/Nr-CAM was described by Grumet et al. (1991) and Kayyem et al. (1992) and shown to play a role in nervous system development. The protein interacts with other cell surface molecules of the Ig superfamily and appears to be necessary for specific pathfinding by axonal growth cones during development (Lane et al., 1996). Lane et al. (1996) cloned the human homolog (NRCAM) of the chicken gene from a fetal brain library. Like its chicken counterpart, the predicted 1,275-amino acid protein has 6 V-like Ig domains and 5 fibronectin type III repeats. The transmembrane and intracellular domains of human and chicken NRCAM are entirely conserved and the proteins are 82% identical overall. Alternative splice variants were observed involving sequence around the fifth fibronectin repeat. Northern blots showed an approximately 7-kb transcript in all tissues of adult human brain examined.
Wang et al. (1998) found expression of a 7.0-kb NRCAM transcript at highest levels in brain, adrenal medulla, and adrenal cortex and at intermediate levels in placenta, pancreas, thyroid, and testis. In a PCR survey of splice variants in fetal and adult tissues, they found spatial and temporal variations in the exons utilized. They noted that this phenomenon is conserved in the chick NrCAM and has been observed in other related CAMs.
Using Western blot analysis, More et al. (2001) showed that Nrcam was prominently expressed in mouse and chick lens during postnatal development, with reduced expression during adulthood. No Nrcam ligands were detected, suggesting that homophilic binding of Nrcam on lens fibers mediated contact between opposing lens fiber membranes.
Using in situ hybridization, Sakurai et al. (2001) showed that Nrcam was expressed on granule and Purkinje cells in developing mouse cerebellum, overlapping with the distribution of L1 (L1CAM; 308840).
By in situ hybridization and immunohistochemical analyses, Williams et al. (2006) showed that Nrcam was most highly expressed throughout development in mouse retinal ganglion cells (RGCs) whose axons projected contralaterally.
Using in situ hybridization, Demyanenko et al. (2014) showed that Nrcam was expressed during postnatal development in mouse visual cortex, with enrichment in layers 4 and 6.
Lokapally et al. (2017) noted that Xenopus Nrcam has a protein structure similar to that of NRCAM in other vertebrates, except that it lacks the 5th fibronectin-type III repeat and is expressed exclusively in nervous system. RT-PCR analysis revealed that Xenopus Nrcam was most abundantly expressed along the dorsal midline throughout developing brain and in the outer nuclear layer of retina.
Using in situ hybridization and immunostaining analyses, Harley et al. (2018) showed that Nrcam was expressed on spiral ganglion neuron (SGN) afferent and olivocochlear efferent fibers, as well as on membranes of developing hair and supporting cells, throughout cochlear innervation during embryonic and early postnatal development in mice.
Dry et al. (2001) determined that the NRCAM gene contains 34 exons spanning over 316 kb.
By fluorescence in situ hybridization, Lane et al. (1996) mapped the NRCAM gene to 7q31.1-q31.2. By radiation hybrid analysis, Wang et al. (1998) mapped the NRCAM gene close to marker D7S666, which Dry et al. (2001) noted is located at 7q31.
Using immunofluorescence analysis, Custer et al. (2003) showed that Nrcam acted as a pioneer molecule in formation of the node of Ranvier during early development of the peripheral nervous system (PNS) in mice. Nrcam transitioned from sites with Nrcam alone to regions of colocalization with Na+ channels. Loss of Nrcam in mice resulted in a significant developmental delay in clustering both Na+ channels and ankyrin-G (ANK3; 600465) at PNS nodes of Ranvier. The action of Nrcam was manifest locally at individual nodes, rather than affecting overall neuronal expression, and was linked to glial interactions. During remyelination, Na+ channel clusters at new nodes were initially labile, and anchoring to the cytoskeleton appeared to grow progressively with time. Measurement of the rate of Schwann cell growth during remyelination revealed that the distance between Na+ channel clusters across remyelinating Schwann cells increased markedly during node formation, indicating that loci of nodes were not fixed in advance by the axon. Based on these results, the authors proposed that axonal Na+ channels moved by lateral diffusion from regions of Schwann-cell contact for node formation, with clustering dependent on linkage to the cytoskeleton by ankyrin-G. Computational analysis supported this model and showed that it needed fast kinetics. The early arrival of Nrcam contributed to this requirement for fast kinetics, and as a result, Nrcam deletion caused a delay in both Na+ channels and ankyrin-G during the node of Ranvier formation in mice.
By analyzing cultured semi-intact visual system preparations from mouse embryos, Williams et al. (2006) showed that blocking Nrcam function caused a failure of retinal axons to cross the midline and increased a higher proportion of RGC axons to project ipsilaterally. Nrcam functioned primarily in retina and facilitated growth of contralateral axons on chiasm cells. When Nrcam function was blocked, chiasm cells became a less-permissive growth substrate for axons that normally project contralaterally, leading to increased size of the ipsilateral projection. Analysis with Nrcam -/- mice confirmed that Nrcam influenced pathway selection in vivo, as Nrcam -/- mice displayed an age-dependent increase in the size of the ipsilateral projection. Further analysis indicated that Nrcam function was required only by axons originating from the ventrotemporal crescent (VTC) at a specific late stage of development. Restriction of Nrcam function only to the late VTC was likely expression and overlapping functions of other L1 and contactin family CAMs in regions other than VTC. Further analysis demonstrated that Nrcam and Ephb1 (600660) contributed to proper formation of binocular visions through independent pathways.
Demyanenko et al. (2014) found that Nrcam regulated dendritic spine density on pyramidal neurons in mouse visual cortex. Dendritic spine density was elevated in pyramidal neurons of Nrcam -/- mice due to increased excitatory spine synapse number and neurotransmission. Nrcam regulated Sema3f (601124)-induced spine retraction on apical dendrites of cortical pyramidal neurons by forming a complex in brain with Sema3f receptor subunits Npn2 (NRP2; 602070) and Plexa3 (PLXNA3; 300022). A trans heterozygous genetic interaction test further demonstrated that Sema3f and Nrcam pathways interacted in vivo to regulate spine density in star pyramidal neurons.
In 8 patients from 7 unrelated families with neurodevelopmental disorder with neuromuscular and skeletal abnormalities (NEDNMS; 619833), Kurolap et al. (2022) identified homozygous or compound heterozygous mutations in the NRCAM gene (see, e.g., 601581.0001-601581.0005). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. The families were of various origins, including Muslim Arab, Amish, European, and Libyan Jewish; 3 families were consanguineous. There were nonsense, missense, splice site, and frameshift mutations. Several mutations occurred in the third fibronectin type III domain, suggesting a deleterious effect on protein function. However, functional studies of the variants and studies of patient cells were not performed. The authors noted that the neurologic features of the patients support a role for NRCAM in nervous system development.
Associations Pending Confirmation
For discussion of a possible association between autosomal recessive motor neuropathy with myopathic features (see 619216) and variation in the NRCAM gene, see 601581.0006.
More et al. (2001) found that Nrcam -/- mice were viable and fertile, with normal gross anatomy of nervous system. However, Nrcam -/- mice developed mature cataracts and had reduced body weight and motor disabilities. Histologic analysis revealed that cataracts in Nrcam -/- mice were generated by disorganization of lens fiber cells, followed by cellular disintegration and accumulation of cellular debris. Disorganization of fiber cells became distinct during late embryonic development and included abnormalities of F-actin (102560) and connexin-50 (GJA8; 600897)-containing gap junctions. No significant pathfinding errors of commissural axons at the midline of spinal cord or of proprioceptive axon collaterals were detected. The observations in Nrcam -/- mice were indistinguishable from the disorganization of lens fibers in ankyrin-B (ANK2; 106410)-deficient mice, suggesting that Nrcam and ankyrin-B are required to maintain contact between lens fiber cells.
Independently, Sakurai et al. (2001) found that Nrcam -/- mice were born at the expected mendelian ratio, were viable and fertile, and were indistinguishable in overall body size, activity, and growth rate compared with controls. Histologic analysis of Nrcam -/- cerebellum showed a mild size reduction in specific lobes. Further analysis suggested that lack of obvious defects in Nrcam -/- mice was likely due to compensation by closely related CAMs, such as neurofascin (NFASC; 609145) and L1. The authors found that Nrcam and L1 double-knockout mice exhibited severe cerebellar folial defects, as Nrcam and L1 were involved in later stages of cerebellar granule cell development. Mice deficient for both L1 and Nrcam had reduced body weight and an increased rate of postnatal death, especially during the first 1 to 2 weeks after birth. The results suggested overlapping functions for Nrcam and L1. Antibody perturbation of L1 in cultured cerebellar cells from Nrcam -/- mice supported overlapping functions for Nrcam and L1.
Harley et al. (2018) found that cochlea of neonatal Nrcam -/- mice showed errors in type II SGN fasciculation, reduced efferent innervation, and defects in stereotyped packing of hair and supporting cells. Nrcam loss also led to dramatic changes in profiles of presynaptic afferent and efferent synaptic markers at the time of hearing onset. However, Nrcam -/- adults did not show defects in auditory acuity and, by postnatal day-21, developmental deficits in ribbon synapse distribution and sensory domain structure appeared to be corrected in Nrcam -/- mice.
Kurolap et al. (2022) found that loss-of-function mutation of the nrcama gene in zebrafish did not result in gross morphologic defects, but immunostaining of the brain showed a trend toward increased amounts of alpha-tubulin fibers in the dorsal telencephalon, increased thickness of ascending fiber tracts, and alterations in white matter tracts and projections. Mutant larvae showed increased swimming motion during darkness compared to wildtype. The authors concluded that loss of nrcama has neurologic and behavioral effects in zebrafish.
In a 5-year-old boy (P1), born of consanguineous Arab-Muslim parents, with neurodevelopmental disorder with neuromuscular and skeletal abnormalities (NEDNMS; 619833), Kurolap et al. (2022) identified a homozygous c.2785C-T transition (c.2785C-T, NM_001037132.2) in exon 25 of the NRCAM gene, resulting in an arg929-to-ter (R929X) substitution in the fibronectin type III domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in public databases, including gnomAD. Functional studies of the variant and studies of patient cells were not performed. The patient had severe global developmental delay from birth, poor overall growth with microcephaly and dysmorphic facial features, feeding problems, hypotonia, demyelinating polyneuropathy, hydrocephalus, optic and auditory defects, and skeletal anomalies.
In a 21-month-old girl (P2), born of consanguineous Arab-Muslim parents, with neurodevelopmental disorder with neuromuscular and skeletal abnormalities (NEDNMS; 619833), Kurolap et al. (2022) identified a homozygous c.331G-T transversion (c.331G-T, NM_001037132.2) in exon 7 of the NRCAM gene, resulting in a glu111-to-ter (E111X) substitution in the Ig-like-1 domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in public databases, including gnomAD. Functional studies of the variant and studies of patient cells were not performed. The patient had severe global developmental delay, dysmorphic features, feeding difficulties, hypotonia, mild optic and auditory problems, and laryngomalacia. She died at 21 months of age.
In a 14-year-old girl (P5) with neurodevelopmental disorder with neuromuscular and skeletal abnormalities (NEDNMS; 619833), Kurolap et al. (2022) identified compound heterozygous missense mutations in the NRCAM gene: a c.1406A-G transition (c.1406A-G, NM_001037132.2) in exon 15, resulting in an asn469-to-ser (N469S) substitution in the Ig-like-5 domain, and a c.2738G-A transition in exon 25, resulting in a gly913-to-asp (G913D; 601581.0004) substitution in the fibronectin type III domain. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. N469S was present at a low frequency (0.022%) in the gnomAD database, whereas G913D was not present in gnomAD. Functional studies of the variants and studies of patient cells were not performed. The patient had spastic quadriplegia, hip dysplasia, and brain imaging abnormalities.
For discussion of the a c.2738G-A transition (c.2738G-A, NM_001037132.2) in exon 25 of the NRCAM gene, resulting in a gly913-to-asp (G913D) substitution, that was found in compound heterozygous state in a patient with neurodevelopmental disorder with neuromuscular and skeletal abnormalities (NEDNMS; 619833) by Kurolap et al. (2022), see 601581.0003.
In 2 sibs (P6a and 6b), born of consanguineous Libyan Jewish parents, with neurodevelopmental disorder with neuromuscular and skeletal abnormalities (NEDNMS; 619833), Kurolap et al. (2022) identified a homozygous c.590G-A transition (c.590G-A, NM_001037132.2) in exon 9 of the NRCAM gene, resulting in a gly197-to-asp (G197D) substitution in the Ig-like-2 domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was present at a low frequency in the gnomAD database (0.002%). Functional studies of the variant and studies of patient cells were not performed. The patients, who were 41 and 31 years of age, had developmental delay from birth with impaired intellectual development and motor delay. They also had spastic dystonic paraplegia and enlarged ventricles on brain imaging. One sib had epilepsy at 5 years of age.
This variant is classified as a variant of unknown significance because its contribution to a motor neuropathy with myopathic features (see 619216) has not been confirmed.
In 2 brothers (P8a and 8b), born of consanguineous Turkish parents, with juvenile onset of a peripheral motor neuropathy with myopathic features, Kurolap et al. (2022) identified a homozygous c.400T-C transition (c.400T-C, NM_001037132.2) in exon 7 of the NRCAM gene, resulting in a ser134-to-pro (S134P) substitution in the Ig-like-1 domain. The variant, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was not present in the dbSNP, 1000 Genomes Project, or gnomAD databases. Functional studies of the variant and studies of patient cells were not performed. The patients, who were 31 and 27 years of age, had onset of peripheral motor neuropathy at 20 and 15 years of age, respectively. There was secondary myopathic involvement with increased serum creatine kinase. Other features included pes cavus, hammertoes, and scoliosis. One sib had cataracts.
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Demyanenko, G. P., Mohan, V., Zhang, X., Brennaman, L. H., Dharbal, K. E. S., Tran, T. S., Manis, P. B., Maness, P. F. Neural cell adhesion molecule NrCAM regulates semaphorin 3F-induced dendritic spine remodeling. J. Neurosci. 34: 11274-11287, 2014. [PubMed: 25143608] [Full Text: https://doi.org/10.1523/JNEUROSCI.1774-14.2014]
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More, M. I., Kirsch, F.-P., Rathjen, F. G. Targeted ablation of NrCAM or ankyrin-B results in disorganized lens fibers leading to cataract formation. J. Cell Biol. 154: 187-196, 2001. [PubMed: 11449000] [Full Text: https://doi.org/10.1083/jcb.200104038]
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Williams, S. E., Grumet, M., Colman, D. R., Henkemeyer, M., Mason, C. A., Sakurai, T. A role for Nr-CAM in the patterning of binocular visual pathways. Neuron 50: 535-547, 2006. [PubMed: 16701205] [Full Text: https://doi.org/10.1016/j.neuron.2006.03.037]