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David H Ledbetter - One of the best experts on this subject based on the ideXlab platform.
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14-3-3ε is important for neuronal migration by binding to NUDEL: a molecular explanation for Miller–Dieker Syndrome
Nature Genetics, 2003Co-Authors: Kazuhito Toyo-oka, Aki Shionoya, Michael J. Gambello, Carlos Cardoso, Richard J. Leventer, Heather L. Ward, Ramses Ayala, Li-huei Tsai, William B Dobyns, David H LedbetterAbstract:Heterozygous deletions of 17p13.3 result in the human neuronal migration disorders isolated lissencephaly sequence (ILS) and the more severe Miller–Dieker Syndrome (MDS). Mutations in PAFAH1B1 (the gene encoding LIS1) are responsible for ILS and contribute to MDS, but the genetic causes of the greater severity of MDS are unknown. Here, we show that the gene encoding 14-3-3e (YWHAE), one of a family of ubiquitous phosphoserine/threonine–binding proteins, is always deleted in individuals with MDS. Mice deficient in Ywhae have defects in brain development and neuronal migration, similar to defects observed in mice heterozygous with respect to Pafah1b1. Mice heterozygous with respect to both genes have more severe migration defects than single heterozygotes. 14-3-3e binds to CDK5/p35-phosphorylated NUDEL and this binding maintains NUDEL phosphorylation. Similar to LIS1, deficiency of 14-3-3e results in mislocalization of NUDEL and LIS1, consistent with reduction of cytoplasmic dynein function. These results establish a crucial role for 14-3-3e in neuronal development by sustaining the effects of CDK5 phosphorylation and provide a molecular explanation for the differences in severity of human neuronal migration defects with 17p13.3 deletions.
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risk of abnormal pregnancy outcome in carriers of balanced reciprocal translocations involving the Miller Dieker Syndrome mds critical region in chromosome 17p13 3
American Journal of Medical Genetics, 1999Co-Authors: Toni I Pollin, David H Ledbetter, William B Dobyns, Carol A Crowe, Joan E Baileywilson, Ann C M SmithAbstract:We studied the pedigrees of 14 families segregating a reciprocal translocation with one breakpoint in chromosome 17p13 and the other in the distal region of another autosome. All 14 were ascertained on the basis of an affected index case: 13 had Miller-Dieker Syndrome (MDS) and one had dup(17p). In these 14 families, 38 balanced translocation carriers had 127 pregnancies, corrected for ascertainment bias by the exclusion of all index cases and carriers in the line of descent to the index cases. An abnormal phentotype, unbalanced chromosome constitution, or both, were found in 33 of 127 (26%) pregnancies: 15 of 127 (12%) had MDS and an unbalanced karyotype with del (17p); 9 of 127 (7%) had a less severe phenotype with dup(17p); and 9 were unstudied, although MDS with der(17) was usually suspected based on early death and multiple congenital anomalies. When unexplained pregnancy losses, including miscarriages and stillbirths, were excluded from the total, 33 of 99 (33%) pregnancies were phenotypically or genotypically abnormal. The overall risk of abnormal pregnancy outcome of 26% is in the upper range of the reported risk for unbalanced offspring of carrier parents assessed through liveborn aneuploid offspring [Gardner and Sutherland (1996), Oxford Univ. Press]. The risk increases to 33% when unexplained pregnancy losses are excluded from the total. These results are consistent with Daniel's model of risk based on the size of the unbalanced fragments [Daniel (1985) Clin Genet 28:216-224, Daniel et al. (1989) Am J Med Genet 31:14-53]. Pregnancy losses included 26 miscarriages (20%) and two stillbirths (2%) among the 127 pregnancies, similar to the respective population frequencies of 10-20% and 1%.
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Classical lissencephaly Syndromes: does the face reflect the brain?
Journal of Medical Genetics, 1998Co-Authors: Judith E Allanson, David H Ledbetter, William B DobynsAbstract:Both Miller-Dieker Syndrome and isolated lissencephaly sequence are associated with classical lissencephaly. Both have been shown to be associated with deletions and mutations in LIS1 on 17p. Traditionally, the two disorders have been distinguished by the presence of a characteristic facial appearance in Miller-Dieker Syndrome. The forehead is tall and prominent and may have vertical furrowing. There is narrowing at the temples. Eyes are widely spaced with upward slanting fissures. The nose is very short with anteverted nares. The upper lip is long, wide, and thick. The ears may have minor flattening of the helices. By contrast, these features are not seen in isolated lissencephaly sequence. We have measured five children with Miller-Dieker Syndrome (MDS) and 25 children and adolescents with isolated lissencephaly sequence (ILS). Z score (standard deviation score) pattern profiles have been formulated and compared. Patients with ILS at all ages show reduced head circumference, a round head, and a wide and flat face with a broad nose and widely spaced eyes. The most unexpected finding is the similarity of pattern profiles of ILS and MDS in the age group 6 months to 4 years. Correlation coefficient is 0.812 (p
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a revision of the lissencephaly and Miller Dieker Syndrome critical regions in chromosome 17p13 3
Human Molecular Genetics, 1997Co-Authors: Samuel S Chong, William B Dobyns, Akira Tanigami, Anna V Roschke, Svetlana Pack, Romeo Carrozzo, Ann C M Smith, David H LedbetterAbstract:: Miller-Dieker Syndrome (MDS) is a multiple malformation Syndrome characterized by classical lissencephaly and a characteristic facies. It is associated with visible or submicroscopic deletions within chromosome band 17p13.3. Lissencephaly without facial dysmorphism has also been observed and is referred to as isolated lissencephaly sequence (ILS). Apparently partial and non-overlapping deletions of the 5' or 3' end of a candidate gene LIS1 in one ILS and one MDS patient had suggested that MDS was a single gene disorder, and that LIS1 spans in excess of 400 kb. However, the originally presumed 5' end of LIS1 was found to belong to the 14-33 epsilon gene residing more distally on 17p13.3. We have now isolated the correct 5' end of LIS1, constructed a approximately 500 kb genomic contig encompassing LIS1, and estimated its gene to be approximately 80 kg. Fluorescence in situ hybridization analysis of an ILS patient with a de novo balanced translocation, as well as analysis of several other key MDS and ILS deletion patients, localizes the lissencephaly critical region within the LIS1 gene. Therefore, LIS1 remains the strongest candidate gene for the lissencephaly phenotype in ILS and MDS. Our analyses also suggest that additional genes distal to LIS1 may be responsible for the facial dysmorphology and other abnormalities seen in MDS but not in ILS patients, supporting our original concept MDS as a contiguous gene deletion Syndrome.
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point mutations and an intragenic deletion in lis1 the lissencephaly causative gene in isolated lissencephaly sequence and Miller Dieker Syndrome
Human Molecular Genetics, 1997Co-Authors: Cristiana Lo Nigro, William B Dobyns, Samuel S Chong, Romeo Carrozzo, Ann C M Smith, David H LedbetterAbstract:: Classical lissencephaly (smooth brain) or generalized agyria-pachygyria is a severe brain malformation which results from an arrest of neuronal migration at 9-13 weeks gestation. It has been observed in several malformation Syndromes including Miller-Dieker Syndrome (MDS) and isolated lissencephaly sequence (ILS). A gene containing beta-transducin like repeats, now known as LIS1, was previously mapped to the ILS/MDS chromosome region on 17p13.3. We recently localized the classical lissencephaly critical region to the LIS1 gene locus by molecular analysis of key ILS and MDS patients. We have now characterized the structure of LIS1, which consists of 11 exons, and have searched for the presence of subtle mutations in 19 ILS patients who showed no gross rearrangements of LIS1. Single strand conformational polymorphism (SSCP) analysis revealed band-shifts for three patients, each involving a different coding exon, which were not observed in their respective parental DNAs. Sequence analysis identified these de novo mutations as dA --> dG transition in exon VI at nucleotide 446, a dC --> dT transition in exon VIII at nucleotide 817, and a 22 bp deletion at the exon IX-intron 9 junction from nucleotide 988 to 1,002+7, which causes skipping of exon IX in the mature LIS1 transcript. These changes are predicted to result in an H149R amino acid substitution, an R273X premature translation termination, and abolition of amino acids 301-334, in the respective LIS1 proteins. These data thus confirm LIS1 as the gene responsible for classical lissencephaly in ILS and MDS.
Stephen B Baylin - One of the best experts on this subject based on the ideXlab platform.
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mice deficient in the candidate tumor suppressor gene hic1 exhibit developmental defects of structures affected in the Miller Dieker Syndrome
Human Molecular Genetics, 2000Co-Authors: Mark G Carter, Margaret A Johns, Xiaobei Zeng, Li Zhou, Christine M Zink, Joseph L Mankowski, David M Donovan, Stephen B BaylinAbstract:: HIC1 is a candidate tumor suppressor gene which is frequently hypermethylated in human tumors, and its location within the Miller-Dieker Syndrome's critical deletion region at chromosome 17p13.3 makes it a candidate gene for involvement in this gene deletion Syndrome. To study the function of murine Hic1 in development, we have created Hic1 -deficient mice. These animals die perinatally and exhibit varying combinations of gross developmental defects throughout the second half of development, including acrania, exencephaly, cleft palate, limb abnormalities and omphalocele. These findings demonstrate a role for Hic1 in the development of structures affected in the Miller-Dieker Syndrome, and provide functional evidence to strengthen its candidacy as a gene involved in this disorder.
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Mice deficient in the candidate tumor suppressor gene Hic1 exhibit developmental defects of structures affected in the Miller–Dieker Syndrome
Human Molecular Genetics, 2000Co-Authors: Mark G Carter, Margaret A Johns, Xiaobei Zeng, Li Zhou, Joseph L Mankowski, David M Donovan, M. Christine Zink, Stephen B BaylinAbstract:: HIC1 is a candidate tumor suppressor gene which is frequently hypermethylated in human tumors, and its location within the Miller-Dieker Syndrome's critical deletion region at chromosome 17p13.3 makes it a candidate gene for involvement in this gene deletion Syndrome. To study the function of murine Hic1 in development, we have created Hic1 -deficient mice. These animals die perinatally and exhibit varying combinations of gross developmental defects throughout the second half of development, including acrania, exencephaly, cleft palate, limb abnormalities and omphalocele. These findings demonstrate a role for Hic1 in the development of structures affected in the Miller-Dieker Syndrome, and provide functional evidence to strengthen its candidacy as a gene involved in this disorder.
Jonathan L Hecht - One of the best experts on this subject based on the ideXlab platform.
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neocortical neuronal arrangement in Miller Dieker Syndrome
Acta Neuropathologica, 2006Co-Authors: Volney L Sheen, Russell J Ferland, Jason Neal, Megan Harney, Robert Sean Hill, Alison H Banham, Phillip G Brown, Anjen Chenn, Joseph C Corbo, Jonathan L HechtAbstract:Miller Dieker Syndrome (MDS, type I lissencephaly) is a neuronal migration disorder, which is caused by deletions along the short arm of chromosome 17 (17p13.3). Recent studies would suggest that the cortical lamination in MDS is inverted, based on morphological criteria. The present neuropathological study examines the cerebral cortex from a 33-week old fetus with MDS using both neuronal and laminar-specific markers. These expression studies demonstrate a relatively preserved cortex and cortical lamination, overlying a layer of immature neurons in MDS brain. The findings are consistent with both a migratory and proliferative defect, giving rise to lissencephaly. Moreover, characterization of such rare human malformations of cortical development by immunohistochemical techniques will provide a greater understanding of the underlying mechanisms.
William B Dobyns - One of the best experts on this subject based on the ideXlab platform.
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interneuron deficits in patients with the Miller Dieker Syndrome
Acta Neuropathologica, 2005Co-Authors: Maclean M Pancoast, William B Dobyns, Jeffrey A GoldenAbstract:Lissencephaly is characterized by a thickened cortex and loss of gyri, resulting in the brain having a smooth surface. Patients with lissencephaly frequently exhibit epilepsy and mental retardation, conditions often associated with a defect in inhibitory neurons. While lissencephaly has traditionally been considered a disorder of radial migration, recent data indicate interneurons migrate non-radially, while projection neurons migrate radially. To determine if an interneuron defect, and therefore a non-radial migration defect, exists in patients with lissencephaly, we studied the calretinin-expressing interneuron subpopulation in the brains from two fetuses and two children with lissencephaly and a deletion involving 17p13 deletion (Miller-Dieker Syndrome) along with age-matched controls. Our data indicate fetuses with the Miller-Dieker Syndrome have a significant (tenfold) reduction in the number of calretinin-expressing interneurons present, whereas minimal reductions in the number of calretinin-expressing interneurons are present in children with this disorder. These data parallel those seen in the Lis1+/– mouse model of human lissencephaly, and are consistent with a non-radial cell migration defect in humans. Thus, when considering the pathogenesis of human lissencephaly and the clinical manifestations in these patients, defects in both non-radial cell migration (inhibitory interneurons) and radial migration (excitatory projection neurons) must be considered.
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14-3-3ε is important for neuronal migration by binding to NUDEL: a molecular explanation for Miller–Dieker Syndrome
Nature Genetics, 2003Co-Authors: Kazuhito Toyo-oka, Aki Shionoya, Michael J. Gambello, Carlos Cardoso, Richard J. Leventer, Heather L. Ward, Ramses Ayala, Li-huei Tsai, William B Dobyns, David H LedbetterAbstract:Heterozygous deletions of 17p13.3 result in the human neuronal migration disorders isolated lissencephaly sequence (ILS) and the more severe Miller–Dieker Syndrome (MDS). Mutations in PAFAH1B1 (the gene encoding LIS1) are responsible for ILS and contribute to MDS, but the genetic causes of the greater severity of MDS are unknown. Here, we show that the gene encoding 14-3-3e (YWHAE), one of a family of ubiquitous phosphoserine/threonine–binding proteins, is always deleted in individuals with MDS. Mice deficient in Ywhae have defects in brain development and neuronal migration, similar to defects observed in mice heterozygous with respect to Pafah1b1. Mice heterozygous with respect to both genes have more severe migration defects than single heterozygotes. 14-3-3e binds to CDK5/p35-phosphorylated NUDEL and this binding maintains NUDEL phosphorylation. Similar to LIS1, deficiency of 14-3-3e results in mislocalization of NUDEL and LIS1, consistent with reduction of cytoplasmic dynein function. These results establish a crucial role for 14-3-3e in neuronal development by sustaining the effects of CDK5 phosphorylation and provide a molecular explanation for the differences in severity of human neuronal migration defects with 17p13.3 deletions.
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risk of abnormal pregnancy outcome in carriers of balanced reciprocal translocations involving the Miller Dieker Syndrome mds critical region in chromosome 17p13 3
American Journal of Medical Genetics, 1999Co-Authors: Toni I Pollin, David H Ledbetter, William B Dobyns, Carol A Crowe, Joan E Baileywilson, Ann C M SmithAbstract:We studied the pedigrees of 14 families segregating a reciprocal translocation with one breakpoint in chromosome 17p13 and the other in the distal region of another autosome. All 14 were ascertained on the basis of an affected index case: 13 had Miller-Dieker Syndrome (MDS) and one had dup(17p). In these 14 families, 38 balanced translocation carriers had 127 pregnancies, corrected for ascertainment bias by the exclusion of all index cases and carriers in the line of descent to the index cases. An abnormal phentotype, unbalanced chromosome constitution, or both, were found in 33 of 127 (26%) pregnancies: 15 of 127 (12%) had MDS and an unbalanced karyotype with del (17p); 9 of 127 (7%) had a less severe phenotype with dup(17p); and 9 were unstudied, although MDS with der(17) was usually suspected based on early death and multiple congenital anomalies. When unexplained pregnancy losses, including miscarriages and stillbirths, were excluded from the total, 33 of 99 (33%) pregnancies were phenotypically or genotypically abnormal. The overall risk of abnormal pregnancy outcome of 26% is in the upper range of the reported risk for unbalanced offspring of carrier parents assessed through liveborn aneuploid offspring [Gardner and Sutherland (1996), Oxford Univ. Press]. The risk increases to 33% when unexplained pregnancy losses are excluded from the total. These results are consistent with Daniel's model of risk based on the size of the unbalanced fragments [Daniel (1985) Clin Genet 28:216-224, Daniel et al. (1989) Am J Med Genet 31:14-53]. Pregnancy losses included 26 miscarriages (20%) and two stillbirths (2%) among the 127 pregnancies, similar to the respective population frequencies of 10-20% and 1%.
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Classical lissencephaly Syndromes: does the face reflect the brain?
Journal of Medical Genetics, 1998Co-Authors: Judith E Allanson, David H Ledbetter, William B DobynsAbstract:Both Miller-Dieker Syndrome and isolated lissencephaly sequence are associated with classical lissencephaly. Both have been shown to be associated with deletions and mutations in LIS1 on 17p. Traditionally, the two disorders have been distinguished by the presence of a characteristic facial appearance in Miller-Dieker Syndrome. The forehead is tall and prominent and may have vertical furrowing. There is narrowing at the temples. Eyes are widely spaced with upward slanting fissures. The nose is very short with anteverted nares. The upper lip is long, wide, and thick. The ears may have minor flattening of the helices. By contrast, these features are not seen in isolated lissencephaly sequence. We have measured five children with Miller-Dieker Syndrome (MDS) and 25 children and adolescents with isolated lissencephaly sequence (ILS). Z score (standard deviation score) pattern profiles have been formulated and compared. Patients with ILS at all ages show reduced head circumference, a round head, and a wide and flat face with a broad nose and widely spaced eyes. The most unexpected finding is the similarity of pattern profiles of ILS and MDS in the age group 6 months to 4 years. Correlation coefficient is 0.812 (p
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a revision of the lissencephaly and Miller Dieker Syndrome critical regions in chromosome 17p13 3
Human Molecular Genetics, 1997Co-Authors: Samuel S Chong, William B Dobyns, Akira Tanigami, Anna V Roschke, Svetlana Pack, Romeo Carrozzo, Ann C M Smith, David H LedbetterAbstract:: Miller-Dieker Syndrome (MDS) is a multiple malformation Syndrome characterized by classical lissencephaly and a characteristic facies. It is associated with visible or submicroscopic deletions within chromosome band 17p13.3. Lissencephaly without facial dysmorphism has also been observed and is referred to as isolated lissencephaly sequence (ILS). Apparently partial and non-overlapping deletions of the 5' or 3' end of a candidate gene LIS1 in one ILS and one MDS patient had suggested that MDS was a single gene disorder, and that LIS1 spans in excess of 400 kb. However, the originally presumed 5' end of LIS1 was found to belong to the 14-33 epsilon gene residing more distally on 17p13.3. We have now isolated the correct 5' end of LIS1, constructed a approximately 500 kb genomic contig encompassing LIS1, and estimated its gene to be approximately 80 kg. Fluorescence in situ hybridization analysis of an ILS patient with a de novo balanced translocation, as well as analysis of several other key MDS and ILS deletion patients, localizes the lissencephaly critical region within the LIS1 gene. Therefore, LIS1 remains the strongest candidate gene for the lissencephaly phenotype in ILS and MDS. Our analyses also suggest that additional genes distal to LIS1 may be responsible for the facial dysmorphology and other abnormalities seen in MDS but not in ILS patients, supporting our original concept MDS as a contiguous gene deletion Syndrome.
David Chitayat - One of the best experts on this subject based on the ideXlab platform.
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Prenatal ultrasound findings of lissencephaly associated with Miller–Dieker Syndrome and comparison with pre‐ and postnatal magnetic resonance imaging
Ultrasound in Obstetrics & Gynecology, 2004Co-Authors: Katherine Fong, Susan Blaser, Sangeet Ghai, Elizabeth J T Winsor, David ChitayatAbstract:Objective To report on the prenatal ultrasound findings in fetuses with lissencephaly associated with Miller–Dieker Syndrome (MDS) and to compare these findings with those of magnetic resonance imaging (MRI). Methods Cases of MDS confirmed by postnatal chromosome microdeletion analysis were identified through review of patient records. Prenatal ultrasound scans were reviewed retrospectively by two radiologists. For cerebral cortical development, the Sylvian, parieto-occipital and calcarine fissures, and the cingulate sulcus and sulci over the cerebral convexity were evaluated. If one or more of these fissures or sulci were not visualized at the expected gestational age or their appearance was abnormal for gestational age, cortical development was considered delayed. Prenatal and postnatal MRI examinations were reviewed by a pediatric neuroradiologist. Results There were seven cases of MDS. In three cases, the prenatal diagnosis of agyria/lissencephaly was prospectively suspected by ultrasound at 23, 26 and 30 weeks, and subsequently confirmed by prenatal MRI. When we retrospectively reviewed the prenatal ultrasound scans of all fetuses, all had delayed cortical development identified on ultrasound performed after 23 weeks' gestation. In all cases the Sylvian fissure was abnormal on both ultrasound and MRI. In one fetus, a normal cortical appearance for gestational age was seen at the initial 20-week ultrasound examination, but delayed cortical development was identified at a 24-week scan. Mild ventriculomegaly was seen in six fetuses and dysgenesis of the corpus callosum in one. Extracranial abnormalities were detected in five fetuses. Delayed cortical development was seen in two fetuses with mild ventriculomegaly, but no other fetal anomalies. Conclusions In fetuses with MDS, delayed cortical development can be suspected on ultrasound as early as 23 weeks' gestation. This finding warrants further investigations including MRI and FISH analysis for chromosome 17p13.3 deletion. Copyright © 2004 ISUOG. Published by John Wiley & Sons, Ltd.
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prenatal ultrasound findings of lissencephaly associated with Miller Dieker Syndrome and comparison with pre and postnatal magnetic resonance imaging
Ultrasound in Obstetrics & Gynecology, 2004Co-Authors: Katherine Fong, Susan Blaser, Sangeet Ghai, Elizabeth J T Winsor, David ChitayatAbstract:Objective To report on the prenatal ultrasound findings in fetuses with lissencephaly associated with Miller–Dieker Syndrome (MDS) and to compare these findings with those of magnetic resonance imaging (MRI). Methods Cases of MDS confirmed by postnatal chromosome microdeletion analysis were identified through review of patient records. Prenatal ultrasound scans were reviewed retrospectively by two radiologists. For cerebral cortical development, the Sylvian, parieto-occipital and calcarine fissures, and the cingulate sulcus and sulci over the cerebral convexity were evaluated. If one or more of these fissures or sulci were not visualized at the expected gestational age or their appearance was abnormal for gestational age, cortical development was considered delayed. Prenatal and postnatal MRI examinations were reviewed by a pediatric neuroradiologist. Results There were seven cases of MDS. In three cases, the prenatal diagnosis of agyria/lissencephaly was prospectively suspected by ultrasound at 23, 26 and 30 weeks, and subsequently confirmed by prenatal MRI. When we retrospectively reviewed the prenatal ultrasound scans of all fetuses, all had delayed cortical development identified on ultrasound performed after 23 weeks' gestation. In all cases the Sylvian fissure was abnormal on both ultrasound and MRI. In one fetus, a normal cortical appearance for gestational age was seen at the initial 20-week ultrasound examination, but delayed cortical development was identified at a 24-week scan. Mild ventriculomegaly was seen in six fetuses and dysgenesis of the corpus callosum in one. Extracranial abnormalities were detected in five fetuses. Delayed cortical development was seen in two fetuses with mild ventriculomegaly, but no other fetal anomalies. Conclusions In fetuses with MDS, delayed cortical development can be suspected on ultrasound as early as 23 weeks' gestation. This finding warrants further investigations including MRI and FISH analysis for chromosome 17p13.3 deletion. Copyright © 2004 ISUOG. Published by John Wiley & Sons, Ltd.
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omphalocele in Miller Dieker Syndrome expanding the phenotype
American Journal of Medical Genetics, 1997Co-Authors: David Chitayat, Riyana Babul, Susan Blaser, Shiraz Moola, Daniel Yarkoni, Mathew Sermer, Joann Johnson, Jiri Vasjar, Ikuko TeshimaAbstract:We report on a patient prenatally diagnosed with omphalocele, mild cerebral ventriculomegaly, nuchal fold thickening, and cystic changes in the umbilical cord who was found postnatally to have lissencephaly type I. Prenatal chromosome analysis showed a normal male karyotype; however, postnatal high resolution banding and FISH analysis, using a probe for locus D17S379 in chromosome region 17p13.3, demonstrated a deletion at 17p13.3 consistent with Miller-Dieker Syndrome (MDS). A review documented four more cases with MDS/isolated lissencephaly/17p-, with omphalocele. Because MDS is a contiguous gene disorder, we speculate that a gene or genes in this region have a major role in the closure of the lateral folds or the return of the midgut from the body stalk to the abdomen at 5–11 weeks of gestation. Prenatal diagnosis of omphalocele with mild ventriculomegaly should prompt FISH analysis for a deletion in 17p13.3. Am. J. Med. Genet. 69:293–298, 1997. © 1997 Wiley-Liss, Inc.