The Experts below are selected from a list of 14013111 Experts worldwide ranked by ideXlab platform
William B. Dobyns - One of the best experts on this subject based on the ideXlab platform.
-
Bi-allelic Loss of Human APC2, Encoding Adenomatous Polyposis Coli Protein 2, Leads to Lissencephaly, Subcortical Heterotopia, and Global Developmental Delay
American journal of human genetics, 2019Co-Authors: Sangmoon Lee, Nataliya Donato, Dillon Y. Chen, Maha S. Zaki, Reza Maroofian, Henry Houlden, Dalia Abdin, Heba Morsy, Ghayda Mirzaa, William B. DobynsAbstract:Lissencephaly is a severe brain malformation in which failure of neuronal migration results in agyria or pachygyria and in which the brain surface appears unusually smooth. It is often associated with microcephaly, profound intellectual disability, epilepsy, and impaired motor abilities. Twenty-two genes are associated with lissencephaly, accounting for approximately 80% of disease. Here we report on 12 individuals with a unique form of lissencephaly; these individuals come from eight unrelated families and have bi-allelic mutations in APC2, encoding adenomatous polyposis coli protein 2. Brain imaging studies demonstrate extensive posterior predominant lissencephaly, similar to PAFAH1B1-associated lissencephaly, as well as co-occurrence of subcortical heterotopia posterior to the caudate nuclei, "ribbon-like" heterotopia in the posterior frontal region, and dysplastic in-folding of the mesial occipital cortex. The established role of APC2 in integrating the actin and microtubule cytoskeletons to mediate cellular morphological changes suggests shared function with other lissencephaly-encoded cytoskeletal proteins such as α-N-catenin (CTNNA2) and platelet-activating factor acetylhydrolase 1b regulatory subunit 1 (PAFAH1B1, also known as LIS1). Our findings identify APC2 as a radiographically distinguishable recessive form of lissencephaly.
-
Tubulinopathies continued: refining the phenotypic spectrum associated with variants in TUBG1
European Journal of Human Genetics, 2018Co-Authors: Stefanie Brock, Katrien Stouffs, Emmanuel Scalais, Marc D’hooghe, Kathelijn Keymolen, Renzo Guerrini, William B. Dobyns, Nataliya Donato, Anna C. JansenAbstract:Tubulinopathies are a heterogeneous group of conditions with a wide spectrum of clinical severity resulting from variants in genes of the tubulin superfamily. Variants in TUBG1 have been described in three patients with posterior predominant pachygyria and microcephaly. We here report eight additional patients with four novel heterozygous variants in TUBG1 identified by next-generation sequencing (NGS) analysis. All had severe motor and cognitive impairment and all except one developed seizures in early life. The core imaging features included a pachygyric cortex with posterior to anterior gradient, enlarged lateral ventricles most pronounced over the posterior horns, and variable degrees of reduced white matter volume. Basal ganglia, corpus callosum, brainstem, and cerebellum were often normal, in contrast to patients with variants in other tubulin genes where these structures are frequently malformed. The imaging phenotype associated with variants in TUBG1 is therefore more in line with the phenotype resulting from variants in LIS1 (a.k.a. PAFAH1B1 ). This difference may, at least in part, be explained by gamma-tubulin’s physiological function in microtubule nucleation, which differs from that of alpha and beta-tubulin.
-
Lissencephaly: Expanded imaging and clinical classification
American journal of medical genetics. Part A, 2017Co-Authors: Nataliya Donato, Renzo Guerrini, Sara Chiari, Ghayda M. Mirzaa, Kimberly A. Aldinger, Elena Parrini, Carissa Olds, A. James Barkovich, William B. DobynsAbstract:Lissencephaly (“smooth brain,” LIS) is a malformation of cortical development associated with deficient neuronal migration and abnormal formation of cerebral convolutions or gyri. The LIS spectrum includes agyria, pachygyria, and subcortical band heterotopia. Our first classification of LIS and subcortical band heterotopia (SBH) was developed to distinguish between the first two genetic causes of LIS—LIS1 (PAFAH1B1) and DCX. However, progress in molecular genetics has led to identification of 19 LIS-associated genes, leaving the existing classification system insufficient to distinguish the increasingly diverse patterns of LIS. To address this challenge, we reviewed clinical, imaging and molecular data on 188 patients with LIS-SBH ascertained during the last 5 years, and reviewed selected archival data on another ∼1,400 patients. Using these data plus published reports, we constructed a new imaging based classification system with 21 recognizable patterns that reliably predict the most likely causative genes. These patterns do not correlate consistently with the clinical outcome, leading us to also develop a new scale useful for predicting clinical severity and outcome. Taken together, our work provides new tools that should prove useful for clinical management and genetic counselling of patients with LIS-SBH (imaging and severity based classifications), and guidance for prioritizing and interpreting genetic testing results (imaging based- classification).
-
Lissencephaly associated mutations suggest a requirement for the PAFAH1B heterotrimeric complex in brain development
Mechanisms of development, 2000Co-Authors: Kimberley J. Sweeney, Gary D. Clark, William B. Dobyns, Alexander Prokscha, Gregor EicheleAbstract:Human brain malformations, such as Miller-Dieker syndrome (MDS) or isolated lissencephaly sequence (ILS) may result from abnormal neuronal migration during brain development. MDS and ILS patients have a hemizygous deletion or mutation in the LIS1 gene (PAFAH1B1), therefore, the LIS1 encoded protein (Lis1) may play a role in neuronal migration. Lis1 is a subunit of a brain platelet-activating factor acetylhydrolase (PAFAH1B) where it forms a heterotrimeric complex with two hydrolase subunits, referred to as 29 kDa (PAFAH1B3) and 30 kDa (PAFAH1B2). In order to determine whether this heterotrimer is required for the developmental functions of PAFAH1B, we examined the binding properties of 29 and 30 kDa subunits to mutant Lis1 proteins. The results defined the critical regions of Lis1 for PAFAH1B complex formation and demonstrated that all human LIS1 mutations examined resulted in abolished or reduced capacity of Lis1 to interact with the 29 and 30 kDa subunits, suggesting that the PAFAH1B complex participates in the process of neuronal migration.
-
Lissencephaly and subcortical band heterotopia: Molecular basis and diagnosis
Molecular medicine today, 2000Co-Authors: Richard J Leventer, Daniela T Pilz, Naomichi Matsumoto, David H Ledbetter, William B. DobynsAbstract:Magnetic resonance imaging is now used routinely in the evaluation of developmental and neurological disorders and provides exquisite images of the living human brain. Consequently, it is evident that cortical malformations are more common than previously thought. Among the most severe is classical lissencephaly, in which the cortex lacks the complex folding that characterizes the normal human brain. Lissencephaly includes agyria and pachygyria, and merges with subcortical band heterotopia. Current molecular genetic techniques combined with the identification of affected patients have enabled the detection of two of the genes responsible: LIS1 (PAFAH1B1) on chromosome 17 and DCX (doublecortin) on the X chromosome. This review highlights the discovery of these genes and discusses the advances made in understanding the molecular basis of cortical development and improvements in diagnosis and genetic counseling.
Richard J Leventer - One of the best experts on this subject based on the ideXlab platform.
-
14 3 3epsilon is important for neuronal migration by binding to nudel a molecular explanation for miller dieker syndrome
Nature Genetics, 2003Co-Authors: Kazuhito Toyooka, Aki Shionoya, Carlos Cardoso, Heather L. Ward, Richard J Leventer, Michael J Gambello, Ramses AyalaAbstract: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.
-
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, Carlos Cardoso, Heather L. Ward, Ramses Ayala, Li-huei Tsai, Richard J Leventer, Michael J Gambello, 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.
-
Clinical and molecular basis of classical lissencephaly: Mutations in the LIS1 gene (PAFAH1B1).
Human mutation, 2001Co-Authors: Carlos Cardoso, Soma Das, Heather L. Ward, Richard J Leventer, James J. Dowling, June Chung, Kristin Petras, Jessica A. Roseberry, Ann M. Weiss, Christa Lese MartinAbstract:Classical lissencephaly (LIS) and subcortical band heterotopia (SBH) are related cortical malformations secondary to abnormal migration of neurons during early brain development. Approximately 60% of patients with classical LIS, and one patient with atypical SBH have been found to have deletions or mutations of the LIS1 gene, located on 17p13.3. This gene encodes the LIS1 or PAFAH1B1 protein with a coiled-coil domain at the N-terminus and seven WD40 repeats at the C-terminus. It is highly conserved between species and has been shown to interact with multiple proteins involved with cytoskeletal dynamics, playing a role in both cellular division and motility, as well as the regulation of brain levels of platelet activating factor. Here we report 65 large deletions of the LIS1 gene detected by FISH and 41 intragenic mutations, including four not previously reported, the majority of which have been found as a consequence of the investigation of 220 children with LIS or SBH by our group. All intragenic mutations are de novo, and there have been no familial recurrences. Eight-eight percent (36/41) of the mutations result in a truncated or internally deleted protein-with missense mutations found in only 12% (5/41) thus far. Mutations occurred throughout the gene except for exon 7, with clustering of three of the five missense mutations in exon 6. Only five intragenic mutations were recurrent. In general, the most severe LIS phenotype was seen in patients with large deletions of 17p13.3, with milder phenotypes seen with intragenic mutations. Of these, the mildest phenotypes were seen in patients with missense mutations.
-
Mutation analysis of the DCX gene and genotype/phenotype correlation in subcortical band heterotopia
European Journal of Human Genetics, 2001Co-Authors: Naomichi Matsumoto, Julie Kuc, Soma Das, Melissa B Ramocki, Stephanie K Mewborn, L. Dudlicek, Daniela T Pilz, Patti L. Mills, Richard J Leventer, M. Elizabeth RossAbstract:Subcortical band heterotopia (SBH) comprises part of a spectrum of phenotypes associated with classical lissencephaly (LIS). LIS and SBH are caused by alterations in at least two genes: LIS1 (PAFAH1B1) at 17p13.3 and DCX (doublecortin) at Xq22.3–q23. DCX mutations predominantly cause LIS in hemizygous males and SBH in heterozygous females, and we have evaluated several families with LIS male and SBH female siblings. In this study, we performed detailed DCX mutation analysis and genotype–phenotype correlation in a large cohort with typical SBH. We screened 26 sporadic SBH females and 11 LIS/SBH families for DCX mutations by direct sequencing. We found 29 mutations in 22 sporadic patients and 11 pedigrees, including five deletions, four nonsense mutations, 19 missense mutations and one splice donor site mutation. The DCX mutation prevalence was 84.6% (22 of 26) in sporadic SBH patients and 100% (11 of 11) in SBH pedigrees. Maternal germline mosaicism was found in one family. Significant differences in genotype were found in relation to band thickness and familial vs sporadic status.
-
The location and type of mutation predict malformation severity in isolated lissencephaly caused by abnormalities within the LIS1 gene
Human molecular genetics, 2000Co-Authors: Carlos Cardoso, Julie Kuc, Melissa B Ramocki, Stephanie K Mewborn, L. Dudlicek, Naomichi Matsumoto, Patti L. Mills, Richard J Leventer, Lorraine F. May, Soma DasAbstract:Lissencephaly is a cortical malformation secondary to impaired neuronal migration resulting in mental retardation, epilepsy and motor impairment. It shows a severity spectrum from agyria with a severely thickened cortex to posterior band heterotopia only. The LIS1 gene on 17p13.3 encodes a 45 kDa protein named PAFAH1B1 containing seven WD40 repeats. This protein is required for optimal neuronal migration by two proposed mechanisms: as a microtubule-associated protein and as one subunit of the enzyme platelet-activating factor acetylhydrolase. Approximately 65% of patients with isolated lissencephaly sequence (ILS) show intragenic mutations or deletions of the LIS1 gene. We analyzed 29 non-deletion ILS patients carrying a mutation of LIS1 and we report 15 novel mutations. Patients with missense mutations had a milder lissencephaly grade compared with those with mutations leading to a shortened or truncated protein (P = 0.022). Early truncation/deletion mutations in the putative microtubule-binding domain resulted in a more severe lissencephaly than later truncation/deletion mutations (P < 0.001). Our results suggest that the lissencephaly severity in ILS caused by LIS1 mutations may be predicted by the type and location of the mutation. Using a spectrum of ILS patients, we confirm the importance of specific WD40 repeats and a putative microtubule-binding domain for PAFAH1B1 function. We suggest that the small number of missense mutations identified may be due to underdiagnosis of milder phenotypes and hypothesize that the greater lissencephaly severity seen in Miller-Dieker syndrome may be secondary to the loss of another cortical development gene in the deletion of 17p13.3.
Jože Pižem - One of the best experts on this subject based on the ideXlab platform.
-
Novel ASAP1-USP6, FAT1-USP6, SAR1A-USP6, and TNC-USP6 fusions in primary aneurysmal bone cyst.
Genes chromosomes & cancer, 2020Co-Authors: Daja Šekoranja, Andrej Zupan, Žiga Snoj, David Martinčič, Vladka Salapura, Blaž Mavčič, Ana Katarina Limpel Novak, Jože PižemAbstract:Aneurysmal bone cyst (ABC) is a benign but locally aggressive neoplasm, with a tendency for local recurrence. In contrast to other bone tumors with secondary cystic change, ABC is characterized by USP6 gene rearrangement. There is a growing list of known USP6 fusion partners, characterization of which has been enabled with the advent of next-generation sequencing (NGS). The list of known fusion partners includes CDH11, CNBP, COL1A1, CTNNB1, EIF1, FOSL2, OMD, PAFAH1B1, RUNX2, SEC31A, SPARC, STAT3, THRAP3, and USP9X. Using NGS, we analyzed a series of 11 consecutive ABCs and identified USP6 fusions in all cases, providing further evidence that USP6 fusions are universally present in primary ABCs. We identified four novel fusion partners in five ABCs and confirmed them by RT-PCR and Sanger sequencing, ASAP1, FAT1, SAR1A, and TNC (in two cases). Because of high sensitivity and specificity, detection of a USP6 fusion by NGS may assist in differentiating between ABC and its mimics, especially in small biopsy samples when a definite diagnosis cannot be achieved on morphological grounds alone. Further studies with a large number of cases and follow-up are needed to determine whether different fusion partners are associated with specific clinical and pathologic features of ABCs.
-
Primary aneurysmal bone cyst with a novel SPARC-USP6 translocation identified by next-generation sequencing
Cancer genetics, 2018Co-Authors: Daja Šekoranja, Emanuela Boštjančič, Vladka Salapura, Blaž Mavčič, Jože PižemAbstract:Aneurysmal bone cyst (ABC) is a benign but locally aggressive, mostly pediatric neoplasm, with characteristic USP6 gene rearrangement that distinguishes it from a secondary ABC and other primary bone tumors. With the advent of next-generation sequencing (NGS) technology, several hitherto unknown USP6 fusion partners have been identified in ABC. Accordingly, we present a case of an 18-year-old male with a solid sub-periosteal primary ABC in the diaphysis of the left femur. Using an NGS-based assay, we identified SPARC-USP6 fusion, which has not previously been described in ABC. Including our case, the list of currently known USP6 fusion partners in primary ABC include: CDH11, CNBP, COL1A1, CTNNB1, EIF1, FOSL2, OMD, PAFAH1B1, RUNX2, SEC31A, SPARC, STAT3 and THRAP3.
Naomichi Matsumoto - One of the best experts on this subject based on the ideXlab platform.
-
Mutation analysis of the DCX gene and genotype/phenotype correlation in subcortical band heterotopia
European Journal of Human Genetics, 2001Co-Authors: Naomichi Matsumoto, Julie Kuc, Soma Das, Melissa B Ramocki, Stephanie K Mewborn, L. Dudlicek, Daniela T Pilz, Patti L. Mills, Richard J Leventer, M. Elizabeth RossAbstract:Subcortical band heterotopia (SBH) comprises part of a spectrum of phenotypes associated with classical lissencephaly (LIS). LIS and SBH are caused by alterations in at least two genes: LIS1 (PAFAH1B1) at 17p13.3 and DCX (doublecortin) at Xq22.3–q23. DCX mutations predominantly cause LIS in hemizygous males and SBH in heterozygous females, and we have evaluated several families with LIS male and SBH female siblings. In this study, we performed detailed DCX mutation analysis and genotype–phenotype correlation in a large cohort with typical SBH. We screened 26 sporadic SBH females and 11 LIS/SBH families for DCX mutations by direct sequencing. We found 29 mutations in 22 sporadic patients and 11 pedigrees, including five deletions, four nonsense mutations, 19 missense mutations and one splice donor site mutation. The DCX mutation prevalence was 84.6% (22 of 26) in sporadic SBH patients and 100% (11 of 11) in SBH pedigrees. Maternal germline mosaicism was found in one family. Significant differences in genotype were found in relation to band thickness and familial vs sporadic status.
-
The location and type of mutation predict malformation severity in isolated lissencephaly caused by abnormalities within the LIS1 gene
Human molecular genetics, 2000Co-Authors: Carlos Cardoso, Julie Kuc, Melissa B Ramocki, Stephanie K Mewborn, L. Dudlicek, Naomichi Matsumoto, Patti L. Mills, Richard J Leventer, Lorraine F. May, Soma DasAbstract:Lissencephaly is a cortical malformation secondary to impaired neuronal migration resulting in mental retardation, epilepsy and motor impairment. It shows a severity spectrum from agyria with a severely thickened cortex to posterior band heterotopia only. The LIS1 gene on 17p13.3 encodes a 45 kDa protein named PAFAH1B1 containing seven WD40 repeats. This protein is required for optimal neuronal migration by two proposed mechanisms: as a microtubule-associated protein and as one subunit of the enzyme platelet-activating factor acetylhydrolase. Approximately 65% of patients with isolated lissencephaly sequence (ILS) show intragenic mutations or deletions of the LIS1 gene. We analyzed 29 non-deletion ILS patients carrying a mutation of LIS1 and we report 15 novel mutations. Patients with missense mutations had a milder lissencephaly grade compared with those with mutations leading to a shortened or truncated protein (P = 0.022). Early truncation/deletion mutations in the putative microtubule-binding domain resulted in a more severe lissencephaly than later truncation/deletion mutations (P < 0.001). Our results suggest that the lissencephaly severity in ILS caused by LIS1 mutations may be predicted by the type and location of the mutation. Using a spectrum of ILS patients, we confirm the importance of specific WD40 repeats and a putative microtubule-binding domain for PAFAH1B1 function. We suggest that the small number of missense mutations identified may be due to underdiagnosis of milder phenotypes and hypothesize that the greater lissencephaly severity seen in Miller-Dieker syndrome may be secondary to the loss of another cortical development gene in the deletion of 17p13.3.
-
Lissencephaly and subcortical band heterotopia: Molecular basis and diagnosis
Molecular medicine today, 2000Co-Authors: Richard J Leventer, Daniela T Pilz, Naomichi Matsumoto, David H Ledbetter, William B. DobynsAbstract:Magnetic resonance imaging is now used routinely in the evaluation of developmental and neurological disorders and provides exquisite images of the living human brain. Consequently, it is evident that cortical malformations are more common than previously thought. Among the most severe is classical lissencephaly, in which the cortex lacks the complex folding that characterizes the normal human brain. Lissencephaly includes agyria and pachygyria, and merges with subcortical band heterotopia. Current molecular genetic techniques combined with the identification of affected patients have enabled the detection of two of the genes responsible: LIS1 (PAFAH1B1) on chromosome 17 and DCX (doublecortin) on the X chromosome. This review highlights the discovery of these genes and discusses the advances made in understanding the molecular basis of cortical development and improvements in diagnosis and genetic counseling.
-
Molecular cloning and characterization of the human NUDC gene
Human genetics, 1999Co-Authors: Naomichi Matsumoto, David H LedbetterAbstract:In both Aspergillus nidulans and the mouse, studies of the nuclear distribution gene C (NudC) have strongly suggested that the NudC protein interacts with NudF, which is the product of NudF, a homologue of human LIS1 (also know as PAFAH1B1), one of the causative genes for classical lissencephaly. We have isolated the human NUDC gene and its two processed pseudogenes. The human NUDC gene is highly conserved and its predicted amino acid sequence shows 94% identity to mouse NudC and 95% identity to rat NudC. The genomic structure of NUDC, its chromosomal localization, and expression pattern in human tissues were characterized. NUDC consists of at least 9 exons ranging from 66 bp to 266 bp in size and 8 introns from 92 bp to 2.0 kb in length, and the total genomic region spans about 8 kb. NUDC was mapped to 1p34-p35 by fluorescence in situ hybridization. Northern analysis showed a major 1.6 kb transcript in all fetal and adult tissues examined. Primers which amplify individual exons of NUDC were developed for mutation analysis.
Soma Das - One of the best experts on this subject based on the ideXlab platform.
-
Clinical and molecular basis of classical lissencephaly: Mutations in the LIS1 gene (PAFAH1B1).
Human mutation, 2001Co-Authors: Carlos Cardoso, Soma Das, Heather L. Ward, Richard J Leventer, James J. Dowling, June Chung, Kristin Petras, Jessica A. Roseberry, Ann M. Weiss, Christa Lese MartinAbstract:Classical lissencephaly (LIS) and subcortical band heterotopia (SBH) are related cortical malformations secondary to abnormal migration of neurons during early brain development. Approximately 60% of patients with classical LIS, and one patient with atypical SBH have been found to have deletions or mutations of the LIS1 gene, located on 17p13.3. This gene encodes the LIS1 or PAFAH1B1 protein with a coiled-coil domain at the N-terminus and seven WD40 repeats at the C-terminus. It is highly conserved between species and has been shown to interact with multiple proteins involved with cytoskeletal dynamics, playing a role in both cellular division and motility, as well as the regulation of brain levels of platelet activating factor. Here we report 65 large deletions of the LIS1 gene detected by FISH and 41 intragenic mutations, including four not previously reported, the majority of which have been found as a consequence of the investigation of 220 children with LIS or SBH by our group. All intragenic mutations are de novo, and there have been no familial recurrences. Eight-eight percent (36/41) of the mutations result in a truncated or internally deleted protein-with missense mutations found in only 12% (5/41) thus far. Mutations occurred throughout the gene except for exon 7, with clustering of three of the five missense mutations in exon 6. Only five intragenic mutations were recurrent. In general, the most severe LIS phenotype was seen in patients with large deletions of 17p13.3, with milder phenotypes seen with intragenic mutations. Of these, the mildest phenotypes were seen in patients with missense mutations.
-
Mutation analysis of the DCX gene and genotype/phenotype correlation in subcortical band heterotopia
European Journal of Human Genetics, 2001Co-Authors: Naomichi Matsumoto, Julie Kuc, Soma Das, Melissa B Ramocki, Stephanie K Mewborn, L. Dudlicek, Daniela T Pilz, Patti L. Mills, Richard J Leventer, M. Elizabeth RossAbstract:Subcortical band heterotopia (SBH) comprises part of a spectrum of phenotypes associated with classical lissencephaly (LIS). LIS and SBH are caused by alterations in at least two genes: LIS1 (PAFAH1B1) at 17p13.3 and DCX (doublecortin) at Xq22.3–q23. DCX mutations predominantly cause LIS in hemizygous males and SBH in heterozygous females, and we have evaluated several families with LIS male and SBH female siblings. In this study, we performed detailed DCX mutation analysis and genotype–phenotype correlation in a large cohort with typical SBH. We screened 26 sporadic SBH females and 11 LIS/SBH families for DCX mutations by direct sequencing. We found 29 mutations in 22 sporadic patients and 11 pedigrees, including five deletions, four nonsense mutations, 19 missense mutations and one splice donor site mutation. The DCX mutation prevalence was 84.6% (22 of 26) in sporadic SBH patients and 100% (11 of 11) in SBH pedigrees. Maternal germline mosaicism was found in one family. Significant differences in genotype were found in relation to band thickness and familial vs sporadic status.
-
The location and type of mutation predict malformation severity in isolated lissencephaly caused by abnormalities within the LIS1 gene
Human molecular genetics, 2000Co-Authors: Carlos Cardoso, Julie Kuc, Melissa B Ramocki, Stephanie K Mewborn, L. Dudlicek, Naomichi Matsumoto, Patti L. Mills, Richard J Leventer, Lorraine F. May, Soma DasAbstract:Lissencephaly is a cortical malformation secondary to impaired neuronal migration resulting in mental retardation, epilepsy and motor impairment. It shows a severity spectrum from agyria with a severely thickened cortex to posterior band heterotopia only. The LIS1 gene on 17p13.3 encodes a 45 kDa protein named PAFAH1B1 containing seven WD40 repeats. This protein is required for optimal neuronal migration by two proposed mechanisms: as a microtubule-associated protein and as one subunit of the enzyme platelet-activating factor acetylhydrolase. Approximately 65% of patients with isolated lissencephaly sequence (ILS) show intragenic mutations or deletions of the LIS1 gene. We analyzed 29 non-deletion ILS patients carrying a mutation of LIS1 and we report 15 novel mutations. Patients with missense mutations had a milder lissencephaly grade compared with those with mutations leading to a shortened or truncated protein (P = 0.022). Early truncation/deletion mutations in the putative microtubule-binding domain resulted in a more severe lissencephaly than later truncation/deletion mutations (P < 0.001). Our results suggest that the lissencephaly severity in ILS caused by LIS1 mutations may be predicted by the type and location of the mutation. Using a spectrum of ILS patients, we confirm the importance of specific WD40 repeats and a putative microtubule-binding domain for PAFAH1B1 function. We suggest that the small number of missense mutations identified may be due to underdiagnosis of milder phenotypes and hypothesize that the greater lissencephaly severity seen in Miller-Dieker syndrome may be secondary to the loss of another cortical development gene in the deletion of 17p13.3.
