ABSTRACT
Reelin is an extracellular matrix-associated protein important in the regulation of neuronal migration during cerebral cortical development. Point mutations in the RELN gene have been shown to cause an autosomal recessive human brain malformation termed lissencephaly with cerebellar hypoplasia (LCH). Recent work has raised the possibility that reelin may also play a pathogenic role in other neuropsychiatric disorders. We sought, therefore, to define more precisely the phenotype of RELN gene disruption. To do this, we performed a clinical, radiological, and molecular study of a family in whom multiple individuals carry a chromosomal inversion that disrupts the RELN locus. A 6-year-old girl homozygous for the pericentric inversion 46,XX,inv7(p11.2q22) demonstrated the same clinical features that have been previously described in association with RELN point mutations. The girl's brain magnetic resonance imaging (MRI) findings, including pachygyria and severe cerebellar hypoplasia, were identical to those seen with RELN point mutations. Fluorescence in situ hybridization confirmed that one of the breakpoints of this inversion mapped to within the RELN gene, and Western blotting revealed an absence of detectable serum reelin protein. Several relatives who were heterozygous for this inversion were neurologically normal and had no signs of psychotic illness. Our findings demonstrate the distinctive phenotype of LCH, which is easily distinguishable from other forms of lissencephaly. Although RELN appears to be critical for normal cerebral and cerebellar development, its role, if any, in the pathogenesis of psychiatric disorders remains unclear.
Subject(s)
Brain/abnormalities , Cell Adhesion Molecules, Neuronal/genetics , Extracellular Matrix Proteins/genetics , Nerve Tissue Proteins/genetics , Serine Endopeptidases/genetics , Cell Adhesion Molecules, Neuronal/blood , Cell Adhesion Molecules, Neuronal/deficiency , Cell Adhesion Molecules, Neuronal/physiology , Central Nervous System Diseases/genetics , Cerebellum/abnormalities , Cerebral Cortex/abnormalities , Child , Chromosome Inversion , Chromosomes, Human, Pair 7/genetics , Cytogenetics , Extracellular Matrix Proteins/blood , Extracellular Matrix Proteins/deficiency , Extracellular Matrix Proteins/physiology , Female , Heterozygote , Homozygote , Humans , In Situ Hybridization, Fluorescence , Magnetic Resonance Imaging , Male , Mental Disorders/genetics , Nerve Tissue Proteins/blood , Nerve Tissue Proteins/deficiency , Nerve Tissue Proteins/physiology , Pedigree , Phenotype , Reelin Protein , Serine Endopeptidases/blood , Serine Endopeptidases/deficiency , Serine Endopeptidases/physiologyABSTRACT
BACKGROUND: Cytogenetic studies in patients with reproductive failure AIM: To investigate the contribution of chromosomal abnormalities in sub fertility and in couples with repeated abortions. METHODS: Hundred and 13 couples who had at least two or more spontaneous abortions and 65 women and 63 men with infertility were analyzed cytogenetically. RESULTS: Major chromosomal rearrangements were found in 8% and minor variants in 6% in the study population. Major chromosomal aberrations were judged to explain 4.9% of recurrent abortions and 13% of infertility. Chromosomal abnormalities in infertile men occurred in 5% and in infertile women in 21.5%. The chromosomal abnormalities were structural (57%), numerical (18%) or mosaics (25%). CONCLUSIONS: Chromosomal aberrations in recurrent abortions are mostly structural ones and those in female infertility mosaicism of sex chromosomes. Turner's syndrome, Turner variants and XY females are detected as a cause of female infertility. The structural and numerical aberrations of either sex or autosomal chromosomes were found in infertile men.
