Alternative titles; symbols
HGNC Approved Gene Symbol: CIT
Cytogenetic location: 12q24.23 Genomic coordinates (GRCh38): 12:119,685,791-119,877,320 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q24.23 | Microcephaly 17, primary, autosomal recessive | 617090 | Autosomal recessive | 3 |
Activated Rho GTPases (see 602924) trigger distinctive kinase cascades. In particular, ROCK (see ROCK1, 601702) binds to Rho, and its kinase activity is moderately stimulated by this association. The citron molecule (Madaule et al., 1995), a specific interactor of Rho and Rac (see 602048), shares a significant degree of structural homology with ROCK; however, its lack of a kinase domain raised the question of its biologic function. By PCR of a mouse primary keratinocyte cDNA library, Di Cunto et al. (1998) identified a novel serine/threonine kinase, Crik (citron Rho-interacting kinase), belonging to the myotonic dystrophy kinase (see 605377) family. Mouse Crik can be expressed as at least 2 isoforms, one of which encompasses the previously reported form of citron in almost its entirety. The long form Of Crik is a 240-kD protein in which the kinase domain is followed by the sequence of citron. The short form, Crik-SK (short kinase), is an approximately 54-kD protein that consists mostly of the kinase domain. When expressed in keratinocytes, full-length Crik, but not Crik-SK, localized into corpuscular cytoplasmic structures and elicits recruitment of actin into these structures. The previously reported Rho-associated kinases ROCK1 and ROCK2 (604002) are ubiquitously expressed. Northern blot analysis of mouse tissues revealed a restricted pattern of expression limited to keratinocytes, brain, spleen, lung, kidney, and an especially strong signal in testis. No expression was detectable in heart, liver, or skeletal muscle. The CRIK protein contains a kinase domain, a coiled-coil domain, a leucine-rich domain, a Rho-Rac binding domain, a zinc finger region, a pleckstrin homology domain, and a putative SH3-binding domain. Di Cunto et al. (1998) cloned the human homolog of the CRIK kinase domain.
By screening size-fractionated human brain cDNA libraries for cDNAs encoding proteins larger than 50 kD, Nagase et al. (1999) identified CRIK as cDNA KIAA0949 (GenBank AB023166).
Di Cunto et al. (1998) determined that the mouse Crik and Crik-SK proteins are capable of phosphorylating exogenous substrates as well as of autophosphorylation, when tested by in vitro kinase assays after expression into COS-7 cells. Crik kinase activity was increased several-fold by coexpression of constitutively active Rho, whereas active Rac had more limited effects. Kinase activity of the endogenous CRIK was indicated by in vitro kinase assays after immunoprecipitation with antibodies recognizing the citron moiety of the protein.
Di Cunto et al. (1998) mapped the human CIT gene to chromosome 12q24.1-q24.3. They stated that the human homolog of citron is contained within a PAC clone (GenBank AC002563) mapping to chromosome 12q.
In 8 patients from 3 unrelated consanguineous families with autosomal recessive primary microcephaly-17 (MCPH17; 617090), Li et al. (2016) identified 3 different homozygous missense mutations in the CIT gene (605629.0001-605629.0003). The mutations were found by whole-exome sequencing and segregated with the disorder in the families. In vitro functional expression studies showed that the mutant proteins had no detectable kinase activity, consistent with a loss of function. Patient fibroblasts showed no defects in cell proliferation or mitosis, but patient-derived induced neural progenitor cells showed abnormal cytokinesis with delayed mitosis, cellular blebbing, multipolar spindles, and increased apoptosis. These cellular defects were rescued by expression of the wildtype allele. The findings suggested that this form of microcephaly is caused by impaired cytokinesis during neuronal development, which results in genome instability, genotoxic stress, apoptosis, and subsequently, reduced cerebral volume.
In 3 probands with MCPH17, Harding et al. (2016) identified homozygous or compound heterozygous mutations in the CIT gene (see, e.g., 605629.0004-605629.0005). Two probands, who were born of consanguineous Arab parents and carried homozygous truncating mutations, had a severe form of the disorder with microlissencephaly, agenesis of the corpus callosum, and brainstem and cerebellar hypoplasia; 1 proband and 2 affected sibs died in the newborn period. The proband in the third family, of French descent, was compound heterozygous for a truncating mutation and a missense mutation; this patient had a slightly less severe phenotype and was alive at age 10 years. Harding et al. (2016) noted the phenotypic similarities to the Cit-null mouse (see ANIMAL MODEL).
Di Cunto et al. (2000) generated mice deficient in citron kinase by targeted disruption. Citron-K -/- mice grow at slower rates, are severely ataxic, and die before adulthood as a consequence of fatal seizures. Their brains display defective neurogenesis, with dramatic depletion of microneurons in the olfactory bulb, hippocampus, and cerebellum. These abnormalities arise during development of the central nervous system due to altered cytokinesis and massive apoptosis. Di Cunto et al. (2000) concluded that citron-K is essential for cytokinesis in vivo, in specific neuronal precursors only. Moreover, they suggested a novel molecular mechanism for a subset of human malformation syndromes of the central nervous system.
In 4 sibs, born of consanguineous Egyptian parents (family 718), with autosomal recessive primary microcephaly-17 (MCPH17; 617090), Li et al. (2016) identified a homozygous c.317G-T transversion (c.317G-T, NM_001206999) in exon 4 of the CIT gene, resulting in a gly106-to-val (G106V) substitution at a conserved residue in the kinase domain. The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family and was not found in the ExAC database or in 5,000 geographically matched individuals.
In 3 patients from a consanguineous Egyptian family (family 1379), with autosomal recessive primary microcephaly-17 (MCPH17; 617090), Li et al. (2016) identified a homozygous c.376A-C transversion (c.376A-C, NM_001206999) in the CIT gene, resulting in a lys126-to-gln (K126Q) substitution at a conserved residue in the kinase domain. The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family and was not found in the ExAC database or in 5,000 geographically matched individuals.
In a patient, born of consanguineous Turkish parents (family 1924), with autosomal recessive primary microcephaly-17 (MCPH17; 617090), Li et al. (2016) identified a homozygous c.689A-T transversion (c.689A-T, NM_001206999) in the CIT gene, resulting in an asp230-to-val (D230V) substitution at a conserved residue in the kinase domain. The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family and was not found in the ExAC database or in 5,000 geographically matched individuals.
In a patient, born of consanguineous Egyptian parents (family A), with autosomal recessive primary microcephaly-17 (MCPH17; 617090), Harding et al. (2016) identified a homozygous G-to-A transition (c.1111+1G-A, NM_007174.2) in intron 9 of the CIT gene, resulting in aberrant splicing. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family, and was not found in the 1000 Genomes Project, dbSNP (build 141), Exome Variant Server, or ExAC databases.
Shaheen et al. (2016) identified a homozygous c.1111+1G-A mutation (c.1111+1G-A, NM_001206999.1) in the CIT gene in a girl, born of consanguineous Egyptian parents, with MCPH17. The mutation, which was found by a combination of autozygosity mapping and exome sequencing, segregated with the disorder in the family. The patient died at 5 months of age, but analysis of parental cells showed aberrant splicing predicting a large in-frame deletion (Gly353_371delinsAla) in the kinase domain.
In a patient, born of consanguineous Arab parents (family B), with autosomal recessive primary microcephaly-17 (MCPH17; 617090), Harding et al. (2016) identified a homozygous 10-bp deletion (c.29_38delATCCTTTGGA, NM_007174.2) in exon 2 of the CIT gene, resulting in a frameshift and premature termination (Asn10MetfsTer15). The mutation, which was found by sequencing the CIT gene in 35 probands with microcephaly, was not found in the 1000 Genomes Project, dbSNP (build 141), Exome Variant Server, or ExAC databases. DNA from family members was not available for segregation testing, but there was a similarly affected sib.
In a 6-year-old girl, born of consanguineous Saudi Arab parents, with autosomal recessive primary microcephaly-17 (MCPH17; 617090), Shaheen et al. (2016) identified a homozygous A-to-T transversion in intron 7 of the CIT gene (c.753+3A-T, NM_001206999.1), resulting in aberrant splicing and premature termination (Asp221Ter) in the protein kinase domain. The mutation, which was found by combination of autozygosity mapping and exome sequencing, was filtered against the 1000 Genomes Project, Exome Variant Server, and ExAC databases, and segregated with the disorder in the family. It was not found in 817 in-house ethnically-matched control exomes.
Basit et al. (2016) identified a homozygous c.753+3A-T mutation (c.753+3A-T, NM_001206999) in the CIT gene in 4 sibs, born of consanguineous Saudi parents, with MCPH17. The mutation, 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 not found in the dbSNP or ExAC database.
Basit, S., Al-Harbi, K. M., Alhijji, S. A. M., Albalawi, A. M., Alharby, E., Eldardear, A., Samman, M. I. CIT, a gene involved in neurogenic cytokinesis, is mutated in human primary microcephaly. Hum. Genet. 135: 1199-1207, 2016. [PubMed: 27519304] [Full Text: https://doi.org/10.1007/s00439-016-1724-0]
Di Cunto, F., Calautti, E., Hsiao, J., Ong, L., Topley, G., Turco, E., Dotto, G. P. Citron Rho-interacting kinase, a novel tissue-specific ser/thr kinase encompassing the Rho-Rac-binding protein citron. J. Biol. Chem. 273: 29706-29711, 1998. [PubMed: 9792683] [Full Text: https://doi.org/10.1074/jbc.273.45.29706]
Di Cunto, F., Imarisio, S., Hirsch, E., Broccoli, V., Bulfone, A., Migheli, A., Atzori, C., Turco, E., Triolo, R., Dotto, G. P., Silengo, L., Altruda, F. Defective neurogenesis in citron kinase knockout mice by altered cytokinesis and massive apoptosis. Neuron 28: 115-127, 2000. [PubMed: 11086988] [Full Text: https://doi.org/10.1016/s0896-6273(00)00090-8]
Harding, B. N., Moccia, A., Drunat, S., Soukarieh, O., Tubeuf, H., Chitty, L. S., Verloes, A., Gressens, P., El Ghouzzi, V., Joriot, S., Di Cunto, F., Martins, A., Passemard, S., Bielas, S. L. Mutations in citron kinase cause recessive microlissencephaly with multinucleated neurons. Am. J. Hum. Genet. 99: 511-520, 2016. [PubMed: 27453579] [Full Text: https://doi.org/10.1016/j.ajhg.2016.07.003]
Li, H., Bielas, S. L., Zaki, M. S., Ismail, S., Farfara, D., Um, K., Rosti, R. O., Scott, E. C., Tu, S., Chi, N. C., Gabriel, S., Erson-Omay, E. Z., Ercan-Sencicek, A. G., Yasuno, K., Caglayan, A. O., Kaymakcalan, H., Ekici, B., Bilguvar, K., Gunel, M., Gleeson, J. G. Biallelic mutations in citron kinase link mitotic cytokinesis to human primary microcephaly. Am. J. Hum. Genet. 99: 501-510, 2016. [PubMed: 27453578] [Full Text: https://doi.org/10.1016/j.ajhg.2016.07.004]
Madaule, P., Furuyashiki, T., Reid, T., Ishizaki, T., Watanabe, G., Morii, N., Narumiya, S. A novel partner for the GTP-bound forms of rho and rac. FEBS Lett. 377: 243-248, 1995. [PubMed: 8543060] [Full Text: https://doi.org/10.1016/0014-5793(95)01351-2]
Nagase, T., Ishikawa, K., Suyama, M., Kikuno, R., Hirosawa, M., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. XIII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 6: 63-70, 1999. [PubMed: 10231032] [Full Text: https://doi.org/10.1093/dnares/6.1.63]
Shaheen, R., Hashem, A., Abdel-Salam, G. M. H., Al-Fadhli, F., Ewida, N., Alkuraya, F. S. Mutations in CIT, encoding citron rho-interacting serine/threonine kinase, cause severe primary microcephaly in humans. Hum. Genet. 135: 1191-1197, 2016. [PubMed: 27503289] [Full Text: https://doi.org/10.1007/s00439-016-1722-2]