#618522
Table of Contents
A number sign (#) is used with this entry because of evidence that autosomal dominant intellectual developmental disorder-59 (MRD59) is caused by heterozygous mutation in the CAMK2G gene (602123) on chromosome 10q22.
De Ligt et al. (2012) reported a boy with severe intellectual disability with myopia, strabismus, short stature, flat face with narrow forehead, long palpebral fissures, arched eyebrows, sacral dimple, short hands, brachydactyly, and short feet. He walked at age 5 years and started to speak at age 4 years. He also had behavioral abnormalities, including self-mutilation. Laboratory studies suggested mitochondrial dysfunction without mitochondrial gene defects. Proietti Onori et al. (2018) provided follow-up of the patient reported by de Ligt et al. (2012). At age 16.5 years, he had severely impaired intellectual development (IQ less than 35) and very poor speech. He did not have seizures; juvenile-onset glaucoma was noted. Brain imaging showed no structural abnormalities.
Proietti Onori et al. (2018) reported a 5-year-old boy who presented in infancy with generalized hypotonia and developmental delay with impaired speech and language, as well as autism. He had mild dysmorphic features, including relative macrocephaly, prominent capillary vascular malformations on the forehead and glabella, tall forehead, tubular nose with upturned tip, large ears, round cheeks, and facial hypotonia. He did not have seizures, and brain imaging was normal. The authors noted that both this patient and the patient previously reported by de Ligt et al. (2012) had some facial dysmorphisms, though not strikingly similar.
The heterozygous mutations in the CAMK2G gene that were identified in patients with MRD59 by de Ligt et al. (2012) and Proietti Onori et al. (2018) occurred de novo.
In a boy with MRD59, de Ligt et al. (2012) identified a de novo heterozygous missense mutation in the CAMK2G gene (R292P; 602123.0001). The patient was ascertained from a larger cohort of 100 patients with severe intellectual disability who underwent exome sequencing. Functional studies of the variant were not performed. The patient had normal array and MLL2 testing.
Proietti Onori et al. (2018) identified a de novo heterozygous R292P mutation in a 5-year-old boy with MRD59 and noted that the substitution occurs in an autoregulatory domain that maintains the kinase in an inactive state in the absence of calcium/calmodulin. Detailed in vitro and in vivo functional studies in mouse primary hippocampal cells and in mouse embryos showed that the mutant protein caused decreased neurite length and arborization, as well as impaired neuronal migration from the subventricular zone during development. A dominant effect was observed. Further studies showed that the mutant protein had constitutively increased phosphotransferase activity with increased autophosphorylation at Thr287 compared to controls, consistent with a gain of function. The R292P mutant protein showed impaired nuclear localization, although calmodulin binding was intact. Silencing the catalytic site of the mutant protein reversed the pathogenic effect on neuronal maturation, without rescuing its nuclear targeting. The authors concluded that CAMK2G has an indispensable function in neurodevelopment and that the R292P protein gains constitutive activity toward cytosolic targets, rather than impaired targeting to the nucleus.
de Ligt, J., Willemsen, M. H., van Bon, B. W. M., Kleefstra, T., Yntema, H. G., Kroes, T., Vulto-van Silfhout, A. T., Koolen, D. A., de Vries, P., Gilissen, C., del Rosario, M., Hoischen, A., Scheffer, H., de Vries, B. B. A., Brunner, H. G., Veltman, J. A., Vissers, L. E. L. M. Diagnostic exome sequencing in persons with severe intellectual disability. New Eng. J. Med. 367: 1921-1929, 2012. [PubMed: 23033978, related citations] [Full Text]
Proietti Onori, M., Koopal, B., Everman, D. B., Worthington, J. D., Jones, J. R., Ploeg, M. A., Mientjes, E., van Bon, B. W., Kleefstra, T., Schulman, H., Kushner, S. A., Kury, S., Elgersma, Y., van Woerden, G. M. The intellectual disability-associated CAMK2G p.rg292Pro mutation acts as a pathogenic gain-of-function. Hum. Mutat. 39: 2008-2024, 2018. [PubMed: 30184290, related citations] [Full Text]
Alternative titles; symbols
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 10q22.2 | Intellectual developmental disorder, autosomal dominant 59 | 618522 | Autosomal dominant | 3 | CAMK2G | 602123 |
A number sign (#) is used with this entry because of evidence that autosomal dominant intellectual developmental disorder-59 (MRD59) is caused by heterozygous mutation in the CAMK2G gene (602123) on chromosome 10q22.
De Ligt et al. (2012) reported a boy with severe intellectual disability with myopia, strabismus, short stature, flat face with narrow forehead, long palpebral fissures, arched eyebrows, sacral dimple, short hands, brachydactyly, and short feet. He walked at age 5 years and started to speak at age 4 years. He also had behavioral abnormalities, including self-mutilation. Laboratory studies suggested mitochondrial dysfunction without mitochondrial gene defects. Proietti Onori et al. (2018) provided follow-up of the patient reported by de Ligt et al. (2012). At age 16.5 years, he had severely impaired intellectual development (IQ less than 35) and very poor speech. He did not have seizures; juvenile-onset glaucoma was noted. Brain imaging showed no structural abnormalities.
Proietti Onori et al. (2018) reported a 5-year-old boy who presented in infancy with generalized hypotonia and developmental delay with impaired speech and language, as well as autism. He had mild dysmorphic features, including relative macrocephaly, prominent capillary vascular malformations on the forehead and glabella, tall forehead, tubular nose with upturned tip, large ears, round cheeks, and facial hypotonia. He did not have seizures, and brain imaging was normal. The authors noted that both this patient and the patient previously reported by de Ligt et al. (2012) had some facial dysmorphisms, though not strikingly similar.
The heterozygous mutations in the CAMK2G gene that were identified in patients with MRD59 by de Ligt et al. (2012) and Proietti Onori et al. (2018) occurred de novo.
In a boy with MRD59, de Ligt et al. (2012) identified a de novo heterozygous missense mutation in the CAMK2G gene (R292P; 602123.0001). The patient was ascertained from a larger cohort of 100 patients with severe intellectual disability who underwent exome sequencing. Functional studies of the variant were not performed. The patient had normal array and MLL2 testing.
Proietti Onori et al. (2018) identified a de novo heterozygous R292P mutation in a 5-year-old boy with MRD59 and noted that the substitution occurs in an autoregulatory domain that maintains the kinase in an inactive state in the absence of calcium/calmodulin. Detailed in vitro and in vivo functional studies in mouse primary hippocampal cells and in mouse embryos showed that the mutant protein caused decreased neurite length and arborization, as well as impaired neuronal migration from the subventricular zone during development. A dominant effect was observed. Further studies showed that the mutant protein had constitutively increased phosphotransferase activity with increased autophosphorylation at Thr287 compared to controls, consistent with a gain of function. The R292P mutant protein showed impaired nuclear localization, although calmodulin binding was intact. Silencing the catalytic site of the mutant protein reversed the pathogenic effect on neuronal maturation, without rescuing its nuclear targeting. The authors concluded that CAMK2G has an indispensable function in neurodevelopment and that the R292P protein gains constitutive activity toward cytosolic targets, rather than impaired targeting to the nucleus.
de Ligt, J., Willemsen, M. H., van Bon, B. W. M., Kleefstra, T., Yntema, H. G., Kroes, T., Vulto-van Silfhout, A. T., Koolen, D. A., de Vries, P., Gilissen, C., del Rosario, M., Hoischen, A., Scheffer, H., de Vries, B. B. A., Brunner, H. G., Veltman, J. A., Vissers, L. E. L. M. Diagnostic exome sequencing in persons with severe intellectual disability. New Eng. J. Med. 367: 1921-1929, 2012. [PubMed: 23033978] [Full Text: https://doi.org/10.1056/NEJMoa1206524]
Proietti Onori, M., Koopal, B., Everman, D. B., Worthington, J. D., Jones, J. R., Ploeg, M. A., Mientjes, E., van Bon, B. W., Kleefstra, T., Schulman, H., Kushner, S. A., Kury, S., Elgersma, Y., van Woerden, G. M. The intellectual disability-associated CAMK2G p.rg292Pro mutation acts as a pathogenic gain-of-function. Hum. Mutat. 39: 2008-2024, 2018. [PubMed: 30184290] [Full Text: https://doi.org/10.1002/humu.23647]
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