Alternative titles; symbols
DO: 0070080;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 22q11.21 | {Schizophrenia, susceptibility to, 4} | 600850 | Autosomal dominant | 3 | PRODH | 606810 |
A number sign (#) is used with this entry because susceptibility to schizophrenia-4 (SCZD4) has been associated with mutations in the proline dehydrogenase gene (PRODH; 606810) on chromosome 22q11. Mutations in the PRODH gene also result in hyperprolinemia type I (239500).
For a phenotypic description and a discussion of genetic heterogeneity of schizophrenia, see 181500.
The possibility of linkage for a schizophrenia susceptibility locus (SSL) on chromosome 22q was suggested by independent studies from 2 groups (Pulver et al., 1994; Karayiorgou et al., 1994; Coon et al., 1994), although neither group reported statistically significant linkage results. The fact that the 22q12-q13 region suggested linkage in both studies, as well as in a subsequent study using sib-pair analysis, justified further scrutiny of the region. Furthermore, simulation studies suggested that if heterogeneity exists such that less than 25% of the families are linked to a locus in 22q11-q13, then the currently available linkage data were not adequately powerful to draw firm conclusions (Pulver et al., 1994). Yet additional suspicion of the proximal long arm of chromosome 22 was provided by the report of Pulver et al. (1994) that there is a higher incidence of schizophrenia among patients with velocardiofacial syndrome (VCFS; 192430), a disorder associated with deletion of 22q11.
Knight et al. (2008) reported a consanguineous Pakistani family in which 3 sibs had hearing impairment and partial complex seizures beginning at about 8 years of age, followed by later development of schizophrenia. Another sib had seizures only, and a fifth sib had hearing impairment only. Homozygosity mapping identified a locus on chromosome 2p24 that overlapped with the DFNB47 locus (609946) and a second locus on chromosome 22q12.3-q13.3, near the SCZD4 locus. Sequence analysis excluded mutations in the KCNF1 (603787), ATF4 (604064), and CACNG2 (602911) genes.
Karayiorgou et al. (1995) found and characterized 2 interstitial deletions on 22q11 in a sample of patients with schizophrenia. They estimated the size of the deletions to be between 1.5 and 2 Mb. Both subjects were hemizygous for the markers used, both were female, and both had a history of learning problems as children. Examination of photographs suggested some dysmorphic facial features consistent with the VCFS phenotype. Neither schizophrenic subject had a positive family history of schizophrenia or other psychotic disorders. They were chosen from a Maryland epidemiology sample of schizophrenia patients. In a second study, also reported by Karayiorgou et al. (1995), variation in lesion size in relation to the occurrence of schizophrenia in VCFS was examined. Taken together with the genetic linkage findings, the results suggested that the 22q11 region may harbor genetic lesions that increased the susceptibility to schizophrenia. In a commentary, Propping and Nothen (1995) pointed to the need for independent replication of the findings by methods including fluorescence in situ hybridization studies in large samples of unselected schizophrenia patients and studies using polymorphisms from the deleted region in large samples of schizophrenic patients and parents for the identification of deletions.
A combined analysis of genotypic data from the marker D22S278 in multiply affected schizophrenia families derived from 11 independent research groups showed 252 alleles shared compared with 188 alleles not shared (chi-square 9.31, 1df, P = 0.001) where parental genotype data were known (Schizophrenia Collaborative Linkage Group for Chromosome 22, 1996). This suggested that there is a schizophrenia susceptibility locus at 22q12.
Yan et al. (1998) found 1 child with a chromosome 22q11.2 interstitial deletion among a sample of 32 patients with childhood-onset schizophrenia. Although this child had minimal dysmorphic features, these were only diagnosed after fluorescence in situ hybridization screening demonstrated the deletion. No deletions were found by the same group in a population of 21 children with 'multidimensionally impaired,' a phenotype that consists in part of transient episodes of schizophrenia.
In a genomewide survey of rare copy number variations in schizophrenia, the International Schizophrenia Consortium (2008) identified 13 large deletions (more than 500 kb) in the 22q11.2 deletion interval associated with velocardiofacial syndrome and DiGeorge syndrome (188400) in 3,391 cases of schizophrenia and none in 3,181 controls. The 11 samples consistent with the typical deletions defined an interval with the strongest association (empirical P = 0.0017; genomewide corrected P = 0.0046; odds ratio 21.6). The authors noted that approximately 30% of patients with 22q11.2 deletion-associated phenotypes develop psychosis.
To investigate large copy number variants (CNVs) segregating at rare frequencies (0.1 to 1.0%) in the general population as candidate neurologic disease loci, Itsara et al. (2009) compared large CNVs found in their study of 2,500 individuals with published data from affected individuals in 9 genomewide studies of schizophrenia, autism, and mental retardation. They found evidence to support the association of deletion at chromosome 22q11, in the VCFS region, with autism, mental retardation, and schizophrenia (CNV p = 7.93 x 10(-9)). They identified 31 deletions in this region; all of these were disease-associated.
In 2 sibs with schizophrenia-4 and type I hyperprolinemia, Jacquet et al. (2002) identified a heterozygous deletion of the entire PRODH gene (606810.0001). Two heterozygous mutations in the PRODH gene, leu441 to pro (L441P; 606810.0004) and leu289 to met (L289M; 606810.0003), were identified in 3 of 63 patients with schizophrenia, but not in 68 controls, and were associated with increased plasma proline levels. In the families harboring either the PRODH deletion or the L441P mutation, a second PRODH nucleotide variation cosegregated with higher plasma levels of proline. The authors concluded that type I hyperprolinemia is present in a subset of patients with schizophrenia.
Li et al. (2004) analyzed the PRODH gene in patients with schizophrenia and their families from Sichuan Province in China, comprising 528 family trios and sib pairs. They found association of schizophrenia with 2 haplotypes consisting of the 1945T-C and 1852G-A variants (global p = 0.006) and the 1852G-A and 1766A-G variants (global p = 0.01).
Jacquet et al. (2006) reported a lack of association between hyperprolinemia and childhood-onset schizophrenia in a study of 63 subjects and 62 healthy controls matched for age and sex.
Sigurdsson et al. (2010) studied Df(16)A(+/-) mice, which model a microdeletion on human chromosome 22q11.2 that constitutes one of the largest known genetic risk factors for schizophrenia. To examine functional connectivity in these mice, Sigurdsson et al. (2010) measured the synchronization of neural activity between the hippocampus and the prefrontal cortex during the performance of a task requiring working memory, which is one of the cognitive functions disrupted in the disease. In wildtype mice, hippocampal-prefrontal synchrony increased during working memory performance, consistent with previous reports in rats. Df(16)A(+/-) mice, which are impaired in the acquisition of the task, showed drastically reduced synchrony, measured both by phase-locking of prefrontal cells to hippocampal theta oscillations and by coherence of prefrontal and hippocampal local field potentials. Furthermore, the magnitude of hippocampal-prefrontal coherence at the onset of training could be used to predict the time it took the Df(16)A(+/-) mice to learn the task and increased more slowly during task acquisition. Sigurdsson et al. (2010) concluded that their data suggested how the deficits in functional connectivity observed in patients with schizophrenia may be realized at the single-neuron level, and further suggested that impaired long-range synchrony of neural activity is one consequence of the 22q11.2 deletion and may be a fundamental component of the pathophysiology underlying schizophrenia.
Chun et al. (2014) identified a specific disruption of synaptic transmission at thalamocortical glutamatergic projections in the auditory cortex in murine models of schizophrenia-associated 22q11 deletion syndrome. This deficit is caused by an aberrant elevation of Drd2 (126450) in the thalamus, which renders 22q11 deletion syndrome thalamocortical projections sensitive to antipsychotics and causes a deficient acoustic startle response similar to that observed in schizophrenic patients. Haploinsufficiency of the miRNA-processing gene Dgcr8 (609030) is responsible for the Drd2 elevation and hypersensitivity of auditory thalamocortical projections to antipsychotics. Chun et al. (2014) concluded that this result suggested that DGCR8-miRNA-DRD2-dependent thalamocortical disruption is a pathogenic event underlying schizophrenia-associated psychosis.
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