A Compelling Genetic Hypothesis for a Complex Disease: PRODH2 DGCR6 Variation Leads to Schizophrenia Susceptibility
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Commentary A compelling genetic hypothesis for a complex disease: PRODH2͞DGCR6 variation leads to schizophrenia susceptibility Aravinda Chakravarti* McKusick–Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287 he human genome sequence is facili- lying genes have proved difficult and dis- cation of common sequence variation Ttating the task of identifying disease ease pathophysiology is still in doubt. within and outside the known genes, genes, understanding their normal func- Over the past three decades, scores of called single nucleotide polymorphisms. tions and why compromising their func- psychiatrists and geneticists have grappled Subsequently, to test whether any of the tion is associated with specific features of with identifying the genetic determinants variants were schizophrenia ‘‘markers’’ a disorder and its inheritance pattern (1). of schizophrenia, now universally thought the authors conducted two genetic tests: Genetic disorders with simple dominant to reside at multiple genes (8). These (i) Were the variants in increased fre- and recessive (Mendelian) patterns of in- genetic mapping studies have proved to be quency among schizophrenics as com- heritance are invariably caused by frustrating because no single chromo- pared with controls? (ii) Were the variants rare single-gene mutations that are somal region appears paramount and transmitted by parents to their affected both necessary and sufficient for the dis- genomic locations identified by one group children in significantly greater frequency ease to manifest. However, some single- have seldom been replicated by others. than expected? These genetic tests were gene disorders can display a complex There are many possible reasons for this conducted in three independent and well- pattern of inheritance. outcome, both biolog- documented samples of schizophrenia The prototype for ical and methodologi- cases. These tests led to one inescapable this class is fragile X cal, but heterogeneity The familial nature of conclusion: genetic variation in the 22q11 syndrome (2), whose in disease causation is region increased schizophrenia risk by non-Mendelian and schizophrenia does not conform thought to be the most 2-fold or more. complex pattern of to simple dominant or recessive likely cause. Although the proof is not absolute, the COMMENTARY X-linked inheritance One chromosomal data of Liu et al. (6) strongly suggest that modes of inheritance. arises from dynamic region that appears genetic variation in a specific gene, evolution of the muta- to be contributory to PRODH2, is the likely cause of schizo- tion within families schizophrenia suscep- phrenia susceptibility. The first line of (3). Thus, complexity in inheritance pat- tibility is that on human chromosome evidence comes from the observations terns is not inconsistent with single-gene 22q11 (9). Despite its inconsistent involve- that the strongest association, both by defects although geneticists routinely ment across mapping studies, its impor- elevated frequency and transmission, of equate the non-Mendelian nature of a tance is demonstrated by the finding that schizophrenia is with single nucleotide trait with inheritance at multiple genes 25–31% of patients with microdeletions of polymorphisms within this gene. The sec- (4). Genetic dissection of multigenic dis- chromosomal material at 22q11 met diag- ond piece of evidence is that most of the orders is truly challenging yet possible (5), nostic criteria for schizophrenia and asso- variants in PRODH2 associated with dis- particularly with the human genome se- ciated disorders. These microdeletions are ease are identical to sequences in the quence in hand. In an outstanding piece of rare in the general population but are 80 neighboring pseudogene. Third, in a small sleuthing, Maria Karayiorgou and col- times more frequent in adult schizophren- sample, carriers of variants associated leagues (6) now show that genetic varia- ics and 240 times elevated in childhood- with the disease show elevated plasma tion in proline dehydrogenase on human onset schizophrenia. Although childhood proline levels; it is difficult to know chromosome 22q11 is a likely and signif- onset of schizophrenia is rare, this marked whether brain proline levels are similarly icant cause of schizophrenia. elevation of microdeletion frequency is a affected. As in all studies of complex Schizophrenia is a common and severe terrific clue because it solidly implicates a disorders, caveats abound, but the evi- mental illness of thought, emotion, and genomic region, at least for some cases of dence for PRODH2 culpability in schizo- behavior that affects about 1% of the schizophrenia etiology. The specific genes phrenia is excellent and is more than general population. It is a devastating involved, however, remained a mystery, enough to deserve continued careful scru- disorder, probably unique to humans, af- until the present study (6), because the tiny. PRODH2 encodes proline dehydro- fecting not only the sufferers but also their deletions remove many genes (10). genase, a mitochondrial enzyme that families. The intense familiality of schizo- The success of the Liu et al. (6) study converts proline to ⌬1-pyrroline-5- phrenia has been recognized for a long clearly owes a great deal to the public carboxylate and is involved in transfer of time and siblings of schizophrenics have a availability of the human genome se- redox potential across the mitochondrial 10-fold elevated susceptibility to the phe- quence (11). The authors undertook the membrane. The gene is widely expressed notype (7). The familial nature of schizo- systematic screening of all known nine phrenia does not conform to simple dom- genes in a 1.5 million-bp interval defining inant or recessive modes of inheritance the schizophrenia ‘‘critical’’ interval (10). See companion article on page 3717 in issue 6 of volume 99. and, consequently, identifying the under- This screening involved first the identifi- *E-mail: [email protected]. www.pnas.org͞cgi͞doi͞10.1073͞pnas.092158299 PNAS ͉ April 16, 2002 ͉ vol. 99 ͉ no. 8 ͉ 4755–4756 Downloaded by guest on September 24, 2021 in many tissues, including in the brain, and should be the comprehensive screening of no functional consequences can, on occa- its homozygous deficiency, hyperproline- all genes in a region and the examination of sion, be copied into the functional gene mia, is an inborn error of metabolism. many single nucleotide polymorphisms. Al- and lead to disease (6). If proven, schizo- There is some indication that heterozy- though this is considerable work, even with phrenia, at least the PRODH2 variety, gous deficiency of PRODH2 may be a current genomics technology, Liu et al. (6) arises from the peculiarities of our ge- cause of isolated hyperprolinemia (12). were rewarded by finding multiple markers nome sequence and is a genomic disorder. Importantly, mice created to be homozy- associated with disease in two distinct tests. Thus, some of the complexities in inheri- gous for PRODH2 deficiency demonstrate A low-resolution screen always fails to dis- tance could arise from this feature. a deficit in prepulse inhibition (13), a mea- tinguish between the absence of an effect The recognition that sequence struc- sure of sensorimotor gating affected in and the failure to detect it. Many previous ture affects gene function and this schizo- schizophrenics. Finally, proline may serve as marker association studies in schizophrenia phrenia study could not have been at- a direct modulator of glutamatergic activity were doomed because they examined tempted in the absence of an accurate and in the brain. Thus, the evidence for candi- only one single nucleotide polymorphism finished reference genome sequence for dacy for PRODH2 de- per gene. Fifth, the human chromosome 22 (11). The finished ficiency in schizophre- study of an animal sequence clarifies the gene content and nia is considerable. model, even when it thus allows the systematic gene search The study by Liu et Liu et al. were rewarded by does not demonstrate a strategy. Thus, finishing the human ge- al. (6) is compelling for ‘‘disease’’ phenotype nome sequence remains a top priority. a variety of reasons and finding multiple markers but a biochemical and This is particularly so in the regions that is a wonderful example associated with disease in neural phenotype, is are difficult to finish because they contain of the power of genetic indispensable (13). two distinct tests. a greater frequency of sequence repeats studies in the human. An emerging idea This study has five fea- in human genetics is and duplications. Indeed, these regions tures that are important that of ‘‘genomic dis- may have a surfeit of complex disease to emphasize. First, there is incredible value orders’’ where the mutation results from genes. to clinical genetic studies of apparently rare the specific genomic structure, particu- Liu et al. (6) have raised as many ques- syndromes because they allow us to make larly duplications. This is particularly the tions as they have answered. Chief among cogent genetic hypothesis, such as defi- case with human chromosome 22, which is them is the contribution of PRODH2 to ciency of genetic material in 22q11 predis- extremely rich in segmental duplications schizophrenia risk in the population. Is pose to neuropsychiatric disease. Second, (14). PRODH2 is one example of such PRODH2 deficiency necessary and suffi- there is immense value to well-documented ‘‘paralogous’’ genes on