Isolation of a Miller–Dicker lissencephaly gene containing G protein β-subunit-like repeats

Reiner, Orly; Carrozzo, Romeo; Shen, Ying H.; Wehnert, Manfred; Faustinella, Fabrizia; Dobyns, William B.; Caskey, C. Thomas; Ledbetter, David H.

doi:10.1038/364717a0

Cited by 1,038 publications

(622 citation statements)

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“…In MillerDieker syndrome, lissencephaly results, in part, from disruption of the LIS1 gene. 139,140 In the absence of the Miller-Dieker syndrome, chromosomal deletion, mutations in LIS1 cause a less severe disorder termed isolated lissencephaly sequence (for a review, see Kato and Dobyns 141 ).…”

Section: Lis1 Ndel1 Nde1 and Disc1mentioning

confidence: 99%

The DISC locus in psychiatric illness

et al. 2007

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The DISC locus is located at the breakpoint of a balanced t(1;11) chromosomal translocation in a large and unique Scottish family. This translocation segregates in a highly statistically significant manner with a broad diagnosis of psychiatric illness, including schizophrenia, bipolar disorder and major depression, as well as with a narrow diagnosis of schizophrenia alone. Two novel genes were identified at this locus and due to the high prevalence of schizophrenia in this family, they were named Disrupted-in-Schizophrenia-1 (DISC1) and Disrupted-in-Schizophrenia-2 (DISC2). DISC1 encodes a novel multifunctional scaffold protein, whereas DISC2 is a putative noncoding RNA gene antisense to DISC1. A number of independent genetic linkage and association studies in diverse populations support the original linkage findings in the Scottish family and genetic evidence now implicates the DISC locus in susceptibility to schizophrenia, schizoaffective disorder, bipolar disorder and major depression as well as various cognitive traits. Despite this, with the exception of the t(1;11) translocation, robust evidence for a functional variant(s) is still lacking and genetic heterogeneity is likely. Of the two genes identified at this locus, DISC1 has been prioritized as the most probable candidate susceptibility gene for psychiatric illness, as its protein sequence is directly disrupted by the translocation. Much research has been undertaken in recent years to elucidate the biological functions of the DISC1 protein and to further our understanding of how it contributes to the pathogenesis of schizophrenia. These data are the main subject of this review; however, the potential involvement of DISC2 in the pathogenesis of psychiatric illness is also discussed. A detailed picture of DISC1 function is now emerging, which encompasses roles in neurodevelopment, cytoskeletal function and cAMP signalling, and several DISC1 interactors have also been defined as independent genetic susceptibility factors for psychiatric illness. DISC1 is a hub protein in a multidimensional risk pathway for major mental illness, and studies of this pathway are opening up opportunities for a better understanding of causality and possible mechanisms of intervention. Molecular Psychiatry (2008) 13, 36-64; doi:10.1038/sj.mp.4002106; published online 2 October 2007 Keywords: schizophrenia; bipolar disorder; depression; DISC1; DISC2; mouse models Genetics of DISC1 discoverySt Clair et al. 1 first reported a Scottish family with a high loading of major mental illness, which cosegregates with a t(1;11) translocation. Long-term follow-up of this family over a period of 30 years has reported 87 family members, of whom 37 carry the translocation. 2 Of 29 individuals carrying the translocation, for whom psychiatric assessment was possible, 7 have a diagnosis of schizophrenia, 1 has a diagnosis of bipolar disorder and 10 cases of recurrent major depression were also reported. 2 Thus, 18 of 29 translocation carriers are diagnosed with major mental illness whereas none of...

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Section: Lis1 Ndel1 Nde1 and Disc1mentioning

confidence: 99%

The DISC locus in psychiatric illness

et al. 2007

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“…In humans, lissencephaly has been shown to be caused by mutations in either the genes for Doublecortin (DCX) which is Xlinked 2,3 or LIS1. 4 The mutations usually involve deletions in one allele of the LIS1 gene implying dosage sensitivity for the gene product. 4,5 Subsequently, point mutations were detected as well.…”

Section: Lissencephalymentioning

confidence: 99%

“…4 The mutations usually involve deletions in one allele of the LIS1 gene implying dosage sensitivity for the gene product. 4,5 Subsequently, point mutations were detected as well. [6][7][8] In addition, a patient with an in-frame N-terminal deletion was Correspondence: Dr O Reiner, Department of Molecular Genetics, The Weizmann Institute of Science, 76100 Rehovot, Israel.…”

Section: Lissencephalymentioning

confidence: 99%

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LIS1—no more no less

2002

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“…PAF is also apparently relevant to brain development, since the beta subunit of the PAF inactivating enzyme, bovine PAF acetylhydrolase (PAF-AH), has 99% homology with the human lis-1 gene. The gene codes for a protein related to Miller±Dieker lissencephaly, an inherited neurological disorder that is characterized by the lack of gyri and sulci in the cerebral cortex (Reiner et al 1993;Hattori et al 1994). Taken together, these observations strongly suggest that PAF plays crucial roles in the central nervous system.…”

Section: Introductionmentioning

confidence: 97%