ORPHA: 2512; DO: 0070288;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12q24.23 | Microcephaly 17, primary, autosomal recessive | 617090 | Autosomal recessive | 3 | CIT | 605629 |
A number sign (#) is used with this entry because of evidence that autosomal recessive primary microcephaly-17 (MCPH17) is caused by homozygous or compound heterozygous mutation in the CIT gene (605629) on chromosome 12q24.
Autosomal recessive primary microcephaly-17 (MCPH17) is a severe neurologic disorder characterized by very small head circumference that is apparent at birth and worsens over time (up to -12 SD). Affected individuals have delayed psychomotor development, intellectual disability, spasticity, axial hypotonia, and dysmorphic features. Brain imaging shows a simplified gyral pattern; more severe cases have lissencephaly with hypoplasia of the brainstem and cerebellum (summary by Harding et al., 2016).
For a phenotypic description and a discussion of genetic heterogeneity of primary microcephaly, see MCPH1 (251200).
Li et al. (2016) reported 8 children from 3 unrelated consanguineous families with primary microcephaly. Within the first few years of life, the head circumferences ranged from -5.6 to -8.4 SD. Dysmorphic features included sloping forehead, tubular nose, full lips and cheeks, and large ears. The patients were also noted to have short stature. All patients had delayed psychomotor development with intellectual disability and poor speech. Most had mild hypertonia and hyperreflexia; 1 had severe arthrogryposis. Brain imaging, when performed, showed a simplified gyral pattern and hypogenesis of the corpus callosum.
Harding et al. (2016) reported 6 patients from 3 unrelated families with severe MCPH17 associated with lissencephaly. Four of the patients died in the newborn period. Head circumference, when measured, ranged from -6.5 to -12 SD. The patients who survived showed axial hypotonia and limb hypertonia, delayed development, and dysmorphic facial features, including sloping forehead, large ears, and broad nasal bridge. Brain imaging and/or postmortem examination showed microlissencephaly, agenesis of the corpus callosum, enlarged ventricles, and hypoplasia of the cerebellum and brainstem. Postmortem examination of 1 patient showed a thick cortex, cytologic and organizational abnormalities, and multinucleated neurons, consistent with a defect in cytokinesis during neurodevelopment. In 1 family (family B) of Arab descent, both the proband and an affected deceased sib had renal aplasia or agenesis. The proband in the third family (family C), of French descent, had a slightly less severe phenotype. At age 10 years, he had a head circumference of -6.5 SD, moderate to severe intellectual disability, and mild autistic features.
Basit et al. (2016) reported a consanguineous Saudi family in which 4 sibs, including twins, had MCPH17. They had decreased head circumference (-3 to -6 SD), sloping forehead, mental retardation, and simplified gyral pattern on brain imaging.
Shaheen et al. (2016) reported 2 unrelated children, born of consanguineous Arab parents, with MCPH17. In the first family, ultrasound of the proband at 30 weeks' gestation showed polyhydramnios, intrauterine growth retardation, microcephaly, and absent left kidney. At age 4 months, she had severe microcephaly (-10 SD), short stature, and severe hypertonia with flexion contractures of upper and lower extremities. There was no history of seizures. She died at the age of 5 months; postmortem examination was not performed. The other child was a 6-year-old girl who was noted at birth to have severe microcephaly (-4.6 SD). At age 5 months she developed well-controlled seizures. She continued to have a small head circumference (up to -9 SD), poor overall growth, hypertonia, and spasticity. Brain MRI showed agenesis of corpus callosum, dilated ventricles, diminished white matter, and lissencephaly.
The transmission pattern of MCPH17 in the families reported by Li et al. (2016) was consistent with autosomal recessive inheritance.
In 8 patients from 3 unrelated consanguineous families with MCPH17, 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, 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, born of consanguineous families of Arab descent (families A and B), had homozygous truncating mutations in the CIT gene. The proband in the third family (family C), of French descent, was compound heterozygous for a truncating mutation and a missense mutation; this patient had a slightly less severe phenotype. Harding et al. (2016) noted the phenotypic similarities to the Cit-null mouse (see ANIMAL MODEL).
In 2 unrelated children, born of consanguineous Arab parents, with MCPH17, Shaheen et al. (2016) identified 2 homozygous mutations in the CIT gene (605629.0004 and 605629.0006). The mutations, which were found by a combination of autozygosity mapping and exome sequencing, segregated with the disorder in the families. Both mutations affected the kinase domain.
In 4 sibs, born of consanguineous Saudi parents, with MCPH17, Basit et al. (2016) identified a homozygous splice site mutation in the CIT gene (605629.0006).
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.
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., 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]
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]