Identification of a novel recessive RELN mutation using a homozygous balanced reciprocal translocation

Cornell University, Итак, New York, United States
American Journal of Medical Genetics Part A (Impact Factor: 2.16). 05/2007; 143A(9):939-44. DOI: 10.1002/ajmg.a.31667
Source: PubMed


Two siblings from a consanguineous Egyptian marriage showed an identical phenotype of cortical lissencephaly with cerebellar hypoplasia, severe epilepsy, and mental retardation. Examination of karyotype revealed 46, t(7;12)(q22;p13)mat (7;12)(q22;p13)pat in both affected children, suggesting a homozygous reciprocal balanced translocation. Each healthy parent was a carrier of the balanced translocation in the heterozygous state, suggesting homozygous disruption of a gene involved in brain development. There were early spontaneous abortions in this family, as would be expected from transmission of an unbalanced chromosome. A disruption of RELN at 7q22.1 with absence of encoded protein was identified. This is the first demonstration that such rare homozygous translocations can be used to identify recessive disease gene mutations.

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Available from: Joseph Gleeson, Dec 18, 2013
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    • "Mutation of the RELN gene, coding for the extracellular glycoprotein Reelin, causes a neuronal migration disorder called lissencephaly with cerebellar hypoplasia (Zaki et al., 2007; Guerrini and Parrini, 2010). Reelin binds several receptors, including a complex composed by the apolipoprotein E receptor 2 (ApoER2) and the very low-density lipoprotein receptor (VLDLR) (Honda et al., 2011). "
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    ABSTRACT: Epilepsy is characterized by spontaneous recurrent seizures and comprises a diverse group of syndromes with different etiologies. Epileptogenesis refers to the process whereby the brain becomes epileptic and can be related to several factors, such as acquired structural brain lesions, inborn brain malformations, alterations in neuronal signaling, and defects in maturation and plasticity of neuronal networks. In this review, we will focus on alterations of brain development that lead to an hyperexcitability phenotype in adulthood, providing examples from both animal and human studies. Malformations of cortical development (including focal cortical dysplasia, lissencephaly, heterotopia, and polymicrogyria) are frequently epileptogenic and result from defects in cell proliferation in the germinal zone and/or impaired neuronal migration and differentiation. Delayed or reduced arrival of inhibitory interneurons into the cortical plate is another possible cause of epileptogenesis. GABAergic neurons are generated during early development in the ganglionic eminences, and failure to pursue migration toward the cortex alters the excitatory/inhibitory balance resulting in aberrant network hyperexcitability. More subtle defects in the developmental assembly of excitatory and inhibitory synapses are also involved in epilepsy. For example, mutations in the presynaptic proteins synapsins and SNAP-25 cause derangements of synaptic transmission and plasticity which underlie appearance of an epileptic phenotype. Finally, there is evidence that defects in synapse elimination and remodeling during early "critical periods" can trigger hyperexcitability later in life. Further clarification of the developmental pathways to epilepsy has important implications for disease prevention and therapy.
    Full-text · Article · Mar 2012 · Frontiers in Psychiatry
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    • "Chromosomal translocations may lead to clinical phenotypes via direct gene disruption, formation of chimera genes, or alteration of the expression of genes near the breakpoint via the position effect [5-7]. Several MR-associated genes have been discovered through mapping of the breakpoints of chromosomal translocations, such as the dedicator of cytokinesis 8 gene (DOCK8) at 9p24 [8]; the potassium large conductance calcium-activated channel, subfamily M, alpha member 1 gene (KCNMA1) at 10q22.3 [9]; the autism susceptibility candidate 2 gene (AUTS2) at 7q11.2 [10]; the oligophrenin 1 gene (OPHN1) at Xq12 [11]; the Cdc42 guanine nucleotide exchange factor (GEF) 9 (ARHGEF9) at Xq11.1 [12]; and the reelin gene (RELN) at 7q22 [13]. "
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    ABSTRACT: Chromosome translocation associated with neurodevelopmental disorders provides an opportunity to identify new disease-associated genes and gain new insight into their function. During chromosome analysis, we identified a reciprocal translocation between chromosomes 1p and 12q, t(1; 12)(p32.1; q21.3), co-segregating with microcephaly, language delay, and severe psychomotor retardation in a mother and her two affected boys. Fluorescence in situ hybridization (FISH), long-range PCR, and direct sequencing were used to map the breakpoints on chromosomes 1p and 12q. A reporter gene assay was conducted in human neuroblastoma (SKNSH) and Chinese hamster ovary (CHO) cell lines to assess the functional implication of the fusion sequences between chromosomes 12 and 1. We determined both breakpoints at the nucleotide level. Neither breakpoint disrupted any known gene directly. The breakpoint on chromosome 1p was located amid a gene-poor region of ~ 1.1 Mb, while the breakpoint on chromosome 12q was located ~ 3.4 kb downstream of the ALX1 gene, a homeobox gene. In the reporter gene assay, we discovered that the fusion sequences construct between chromosomes 12 and 1 had a ~ 1.5 to 2-fold increased reporter gene activity compared with the corresponding normal chromosome 12 sequences construct. Our findings imply that the translocation may enhance the expression of the ALX1 gene via the position effect and result in the clinical symptoms of this family. Our findings may also expand the clinical phenotype spectrum of ALX1-related human diseases as loss of the ALX1 function was recently reported to result in abnormal craniofacial development.
    Full-text · Article · May 2011 · BMC Medical Genetics
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    • "The human phenotype is reminiscent of what is observed in homozygous reeler mice, which display ataxia, cerebellar hypoplasia with a decreased number of Purkinje cells, inverted layering of the cortex and abnormal axonal connectivity due to abnormal neuronal migration (see for review [33]). An additional consanguineous pedigree has been reported with an homozygous apparently balanced reciprocal translocation, t(7;12)(q22;p13) disrupting the RELN gene at 7q22.1 [175]. As only three consanguineous families have been described, the clinical phenotype might be wider, and to our knowledge, no neuropathological description is presently available. "
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    ABSTRACT: Type I lissencephaly or agyria-pachygyria is a rare developmental disorder which results from a defect of neuronal migration. It is characterized by the absence of gyri and a thickening of the cerebral cortex and can be associated with other brain and visceral anomalies. Since the discovery of the first genetic cause (deletion of chromosome 17p13.3), six additional genes have been found to be responsible for agyria-pachygyria. In this review, we summarize the current knowledge concerning these genetic disorders including clinical, neuropathological and molecular results. Genetic alterations of LIS1, DCX, ARX, TUBA1A, VLDLR, RELN and more recently WDR62 genes cause migrational abnormalities along with more complex and subtle anomalies affecting cell proliferation and differentiation, i.e., neurite outgrowth, axonal pathfinding, axonal transport, connectivity and even myelination. The number and heterogeneity of clinical, neuropathological and radiological defects suggest that type I lissencephaly now includes several forms of cerebral malformations. In vitro experiments and mutant animal studies, along with neuropathological abnormalities in humans are of invaluable interest for the understanding of pathophysiological mechanisms, highlighting the central role of cytoskeletal dynamics required for a proper achievement of cell proliferation, neuronal migration and differentiation.
    Full-text · Article · Nov 2010 · Acta Neuropathologica
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