The chromosomal translocation (X;18)(p11.2;q11.2) represents the cytogenetic hallmark of human sy... more The chromosomal translocation (X;18)(p11.2;q11.2) represents the cytogenetic hallmark of human synovial sarcomas. Two related but distinct breakpoints within band Xp11.2 were reported previously by us and others using breakpoint-spanning YACs in conjunction with FISH. Interestingly, we found that the occurrence of these alternative breakpoints corresponds to the presence of different histologic characteristics of the tumors involved. Here we report the isolation, via subcloning of one of our YAC-derived cosmids, of probes which specifically hybridize to altered restriction fragments in tumor DNAs as compared to normal controls. By using a synovial sarcoma-derived der(X) containing somatic cell hybrid, which exhibits the more distal breakpoint, one of these aberrantly hybridizing fragments could be isolated via preparative gel electrophoresis. This fragment appears to contain chromosome X- and 18-derived sequences, as revealed by both FISH on normal metaphase spreads and Southern blot analysis of X- and 18-only somatic cell hybrids. We conclude that this genomic fragment is chimaeric in nature and contains the translocation breakpoint region. In addition, our results indicate that, in contrast to our findings on the X chromosome, a single locus on chromosome 18 may be involved in the development of different (sub)types of synovial sarcoma.
SOURCE/DESCRIPTION: An anonymous 0.9 kb EcoRI fragment subcloned into pBR322 (Willard et al, 1983... more SOURCE/DESCRIPTION: An anonymous 0.9 kb EcoRI fragment subcloned into pBR322 (Willard et al, 1983). POLYMORPHISMS: EcoRV (GAT'ATC) identifies two alleles with bands at 7.5 and 4.3 kb. FREQUENCY: 30 unrelated Caucasian women tested.
Genetic factors have an important role in the aetiology of mental retardation. However, their con... more Genetic factors have an important role in the aetiology of mental retardation. However, their contribution is often underestimated because in developed countries, severely affected patients are mainly sporadic cases and familial cases are rare. X-chromosomal mental retardation is the exception to this rule, and this is one of the reasons why research into the genetic and molecular causes of mental retardation has focused almost entirely on the X-chromosome. Here, we review the remarkable recent progress in this field, its promise for understanding neural function, learning and memory, and the implications of this research for health care.
NF-κB is a master regulator of inflammation and has been implicated in the pathogenesis of immune... more NF-κB is a master regulator of inflammation and has been implicated in the pathogenesis of immune disorders and cancer. Its regulation involves a variety of steps, including the controlled degradation of inhibitory IκB proteins. In addition, the inactivation of DNA-bound NF-κB is essential for its regulation. This step requires a factor known as copper metabolism Murr1 domain-containing 1 (COMMD1), the prototype member of a conserved gene family. While COMMD proteins have been linked to the ubiquitination pathway, little else is known about other family members. Here we demonstrate that all COMMD proteins bind to CCDC22, a factor recently implicated in X-linked intellectual disability (XLID). We showed that an XLID-associated CCDC22 mutation decreased CCDC22 protein expression and impaired its binding to COMMD proteins. Moreover, some affected individuals displayed ectodermal dysplasia, a congenital condition that can result from developmental NF-κB blockade. Indeed, patient-derived cells demonstrated impaired NF-κB activation due to decreased IκB ubiquitination and degradation. In addition, we found that COMMD8 acted in conjunction with CCDC22 to direct the degradation of IκB proteins. Taken together, our results indicate that CCDC22 participates in NF-κB activation and that its deficiency leads to decreased IκB turnover in humans, highlighting an important regulatory component of this pathway.
X-linked intellectual disability (XLID), also known as X-linked mental retardation, is a highly g... more X-linked intellectual disability (XLID), also known as X-linked mental retardation, is a highly genetically heterogeneous condition for which mutations in 490 different genes have been identified. In this study, we used a custom-made sequencing array based on the Affymetrix 50k platform for mutation screening in 17 known XLID genes in patients from 135 families and found eight single-nucleotide changes that were absent in controls. For four mutations affecting ATRX (p.1761M4T), PQBP1 (p.155R4X) and SLC6A8 (p.390P4L and p.477S4L), we provide evidence for a functional involvement of these changes in the aetiology of intellectual disability.
We report on a 42-year-old female patient with an interstitial 16 Mb deletion in 7q21.1-21.3 and ... more We report on a 42-year-old female patient with an interstitial 16 Mb deletion in 7q21.1-21.3 and a balanced reciprocal translocation between chromosomes 6 and 7 [karyotype 46,XX,t(6;7)(q23.3;q32.3)del(7)(q21.1q21.3)de novo]. We characterized the size and position of the deletion by tiling path array comparative genomic hybridization (CGH), and we mapped the translocation breakpoints on chromosomes 6 and 7 by FISH. The clinical features of this patient-severe mental retardation, short stature, microcephaly and deafness-are in accordance with previously reported patients with 7q21 deletions. Chromosome band 7q21.3 harbors a locus for split hand/split foot malformation (SHFM1), and part of this locus, including the SHFM1 candidate genes SHFM1, DLX5, and DLX6, is deleted. The absence of limb abnormalities in this patient suggests either a location of the SHFM1 causing factor distal to this deletion, or reduced penetrance of haploinsufficiency of a SHFM1 factor within the deleted interval.
Recently, we showed that truncation of the X-linked cyclin-dependent kinase-like 5 (CDKL5/STK9) g... more Recently, we showed that truncation of the X-linked cyclin-dependent kinase-like 5 (CDKL5/STK9) gene caused mental retardation and severe neurological symptoms in two female patients. Here, we report that de novo missense mutations in CDKL5 are associated with a severe phenotype of early-onset infantile spasms and clinical features that overlap those of other neurodevelopmental disorders, such as Rett syndrome and Angelman syndrome. The mutations are located within the protein kinase domain and affect highly conserved amino acids; this strongly suggests that impaired CDKL5 catalytic activity plays an important role in the pathogenesis of this neurodevelopmental disorder. In view of the overlapping phenotypic spectrum of CDKL5 and MECP2 mutations, it is tempting to speculate that these two genes play a role in a common pathogenic process. In our recent study of two unrelated females with balanced X;autosome translocations, we showed that truncation of the cyclin-dependent kinase-like 5 (CDKL5/ STK9) gene causes a severe phenotype of early-onset infantile spasms, global developmental arrest, and profound mental retardation (Kalscheuer et al. 2003). The phenotypes in these patients are reminiscent of the neonatal-onset encephalopathy seen in several patients with a severe form of atypical Rett syndrome (RTT [MIM 312750]) (Schanen et al. 1998; Villard et al. 2000; Zeev et al. 2002). RTT is a progressive neurodevelopmental disorder that affects almost exclusively girls. The classic form of RTT is characterized by apparently normal development, followed by neurological developmental arrest and regression (Hagberg et al. 1983). The increase in cognitive and motor impairments may continue for
Despite twin and family studies having demonstrated a substantial heritability of individual diff... more Despite twin and family studies having demonstrated a substantial heritability of individual differences in intelligence, no genetic variants have been robustly associated with normal-range intelligence to date. This is largely ascribed to the high polygenicity of intelligence, i.e., to its being subject to the effects of a large number of genes of individually small effect. Intellectual disability, on the other hand, frequently involves large effects of single genetic mutations, many of which have been identified. The present paper aims to 1) introduce the reader to the current state of genetic intelligence research, including next-generation sequencing and the analysis of rare genetic variants, and 2) examine the possible effects of known disability genes on normal-range intelligence. The rationale for the latter rests on the fact that genetic variants affecting continuous, polygenic traits are often concentrated in the same areas of the genome as those underlying related monogenic phenotypes. Using an existing pool of known intellectual disability genes, we constructed a set of 168 candidate genes for normal-range intelligence, and tested their association with intelligence in 191 individuals (aged 5-18) sampled from the high and low ends of the IQ distribution. In particular, we 1) employed exon sequencing to examine the possible effects of rare genetic variants in the 168 genes, and 2) used polygenic prediction to examine the overall effect of common genetic variants in the candidate gene set in a larger sample (N = 2125, mean age 20.4, SD = 14.1). No significant association between the candidate gene set and intelligence was detected.
Pontocerebellar hypoplasia (PCH) is a heterogeneous group of rare recessive disorders with prenat... more Pontocerebellar hypoplasia (PCH) is a heterogeneous group of rare recessive disorders with prenatal onset, characterized by hypoplasia of pons and cerebellum. Mutations in a small number of genes have been reported to cause PCH, and the vast majority of PCH cases are explained by mutations in TSEN54, which encodes a subunit of the tRNA splicing endonuclease complex. Here we report three families with homozygous truncating mutations in TBC1D23 who display moderate to severe intellectual disability and microcephaly. MRI data from available affected subjects revealed PCH, small normally proportioned cerebellum, and corpus callosum anomalies. Furthermore, through in utero electroporation, we show that downregulation of TBC1D23 affects cortical neuron positioning. TBC1D23 is a member of the Tre2-Bub2-Cdc16 (TBC) domain-containing RAB-specific GTPase-activating proteins (TBC/RABGAPs). Members of this protein family negatively regulate RAB proteins and modulate the signaling between RABs a...
Massive parallel sequencing has revolutionized the search for pathogenic variants in the human ge... more Massive parallel sequencing has revolutionized the search for pathogenic variants in the human genome, but for routine diagnosis, re-sequencing of the complete human genome in a large cohort of patients is still far too expensive. Recently, novel genome partitioning methods have been developed that allow to target re-sequencing to specific genomic compartments, but practical experience with these methods is still limited. In this study, we have combined a novel droplet-based multiplex PCR method and next generation sequencing to screen patients with X-linked mental retardation (XLMR) for mutations in 86 previously identified XLMR genes. In total, affected males from 24 large XLMR families were analyzed, including three in whom the mutations were already known. Amplicons corresponding to functionally relevant regions of these genes were sequenced on an Illumina/Solexa Genome Analyzer II platform. Highly specific and uniform enrichment was achieved: on average, 67.9% unambiguously mapped reads were derived from amplicons, and for 88.5% of the targeted bases, the sequencing depth was sufficient to reliably detect variations. Potentially diseasecausing sequence variants were identified in 10 out of 24 patients, including the three mutations that were already known, and all of these could be confirmed by Sanger sequencing. The robust performance of this approach demonstrates the general utility of droplet-based multiplex PCR for parallel mutation screening in hundreds of genes, which is a prerequisite for the diagnosis of mental retardation and other disorders that may be due to defects of a wide variety of genes.
Localization of the gene for X-Iinked Alport's syndrome. X-chromosomal DNA probes defining variou... more Localization of the gene for X-Iinked Alport's syndrome. X-chromosomal DNA probes defining various polymorphic DNA markers were used to study genetic linkage in three families with Alport's syndrome. With the DXS17 marker, only a single cross-over was observed in 26 informative meioses, and evidence for linkage was also obtained with the DXS 11 marker. These data localize the gene for the X-linked form of Alport's syndrome to the middle of the long arm of the X chromosome. Alport's syndrome is characterized by hereditary glomerulo
A balanced translocation was recently identified in a German psoriasis patient. One of the breakp... more A balanced translocation was recently identified in a German psoriasis patient. One of the breakpoints was mapped immediately upstream of the microsomal glutathione S-transferase 2 (MGST2) gene, suggesting it as a candidate gene. Here, we report the identification of a novel non-synonymous mutation in MGST2 by a comprehensive sequence analysis of MGST2's coding region in Chinese psoriasis samples. We demonstrate that this mutation co-segregated with the disease phenotype within a Chinese family affected with psoriasis vulgaris and is predicted to have an impact on the normal function of MGST2 protein. However, the mutation was absent in 551 additional cases and 384 healthy Chinese controls. While requiring independent confirmation, our results suggest that this rare mutation could play a causal role in a small subset of psoriasis individuals.
A family with myoclonus epilepsy has been described previously as suffering from an X-linked diso... more A family with myoclonus epilepsy has been described previously as suffering from an X-linked disorder, because at least four males were affected, and only mild and variable symptoms were seen in some female carriers. In this family, we have now identified a mitochondrial A-~G (8344) heteroplasmic point mutation. This point mutation has been described in families with maternally inherited myoclonus epilepsy and ragged red fibers. The degree of severity of the disorder in the different family members was reflected in the relative quantity of mutated mitochondrial DNA. It is concluded that the mode of inheritance in this family is not X-linked but maternal.
In 16 families with myotonic dystrophy (DM) a novel approach based on use of allele-specific olig... more In 16 families with myotonic dystrophy (DM) a novel approach based on use of allele-specific oligonucleotides has been employed to study the linkage relationship between the apolipoprotein E (APOE) gene and DM. Synthetic oligonucleotides, designed to discriminate between APOE alleles ~3 and ~4, enabled us to distinguish heterozygous carriers in a hybridization assay. In a subset of families, the relevant segment of the APOE gene was enzymatically amplified to increase the sensitivity of the method. For DM and APOE, a maximum lod score (Zmax of 7.47 was obtained at a recombination frequency (0) of 0.047 (male 0 = female 0). No recombination (maximum lod score of 5.61 at 0 = 0.0) was found between APOE and the apolipoprotein CII (APOC2) gene. These results suggest that, in addition to APOC2, APOE is a useful marker for presymptomatic DM diagnosis.
The chromosomal translocation (X;18)(p11.2;q11.2) represents the cytogenetic hallmark of human sy... more The chromosomal translocation (X;18)(p11.2;q11.2) represents the cytogenetic hallmark of human synovial sarcomas. Two related but distinct breakpoints within band Xp11.2 were reported previously by us and others using breakpoint-spanning YACs in conjunction with FISH. Interestingly, we found that the occurrence of these alternative breakpoints corresponds to the presence of different histologic characteristics of the tumors involved. Here we report the isolation, via subcloning of one of our YAC-derived cosmids, of probes which specifically hybridize to altered restriction fragments in tumor DNAs as compared to normal controls. By using a synovial sarcoma-derived der(X) containing somatic cell hybrid, which exhibits the more distal breakpoint, one of these aberrantly hybridizing fragments could be isolated via preparative gel electrophoresis. This fragment appears to contain chromosome X- and 18-derived sequences, as revealed by both FISH on normal metaphase spreads and Southern blot analysis of X- and 18-only somatic cell hybrids. We conclude that this genomic fragment is chimaeric in nature and contains the translocation breakpoint region. In addition, our results indicate that, in contrast to our findings on the X chromosome, a single locus on chromosome 18 may be involved in the development of different (sub)types of synovial sarcoma.
SOURCE/DESCRIPTION: An anonymous 0.9 kb EcoRI fragment subcloned into pBR322 (Willard et al, 1983... more SOURCE/DESCRIPTION: An anonymous 0.9 kb EcoRI fragment subcloned into pBR322 (Willard et al, 1983). POLYMORPHISMS: EcoRV (GAT'ATC) identifies two alleles with bands at 7.5 and 4.3 kb. FREQUENCY: 30 unrelated Caucasian women tested.
Genetic factors have an important role in the aetiology of mental retardation. However, their con... more Genetic factors have an important role in the aetiology of mental retardation. However, their contribution is often underestimated because in developed countries, severely affected patients are mainly sporadic cases and familial cases are rare. X-chromosomal mental retardation is the exception to this rule, and this is one of the reasons why research into the genetic and molecular causes of mental retardation has focused almost entirely on the X-chromosome. Here, we review the remarkable recent progress in this field, its promise for understanding neural function, learning and memory, and the implications of this research for health care.
NF-κB is a master regulator of inflammation and has been implicated in the pathogenesis of immune... more NF-κB is a master regulator of inflammation and has been implicated in the pathogenesis of immune disorders and cancer. Its regulation involves a variety of steps, including the controlled degradation of inhibitory IκB proteins. In addition, the inactivation of DNA-bound NF-κB is essential for its regulation. This step requires a factor known as copper metabolism Murr1 domain-containing 1 (COMMD1), the prototype member of a conserved gene family. While COMMD proteins have been linked to the ubiquitination pathway, little else is known about other family members. Here we demonstrate that all COMMD proteins bind to CCDC22, a factor recently implicated in X-linked intellectual disability (XLID). We showed that an XLID-associated CCDC22 mutation decreased CCDC22 protein expression and impaired its binding to COMMD proteins. Moreover, some affected individuals displayed ectodermal dysplasia, a congenital condition that can result from developmental NF-κB blockade. Indeed, patient-derived cells demonstrated impaired NF-κB activation due to decreased IκB ubiquitination and degradation. In addition, we found that COMMD8 acted in conjunction with CCDC22 to direct the degradation of IκB proteins. Taken together, our results indicate that CCDC22 participates in NF-κB activation and that its deficiency leads to decreased IκB turnover in humans, highlighting an important regulatory component of this pathway.
X-linked intellectual disability (XLID), also known as X-linked mental retardation, is a highly g... more X-linked intellectual disability (XLID), also known as X-linked mental retardation, is a highly genetically heterogeneous condition for which mutations in 490 different genes have been identified. In this study, we used a custom-made sequencing array based on the Affymetrix 50k platform for mutation screening in 17 known XLID genes in patients from 135 families and found eight single-nucleotide changes that were absent in controls. For four mutations affecting ATRX (p.1761M4T), PQBP1 (p.155R4X) and SLC6A8 (p.390P4L and p.477S4L), we provide evidence for a functional involvement of these changes in the aetiology of intellectual disability.
We report on a 42-year-old female patient with an interstitial 16 Mb deletion in 7q21.1-21.3 and ... more We report on a 42-year-old female patient with an interstitial 16 Mb deletion in 7q21.1-21.3 and a balanced reciprocal translocation between chromosomes 6 and 7 [karyotype 46,XX,t(6;7)(q23.3;q32.3)del(7)(q21.1q21.3)de novo]. We characterized the size and position of the deletion by tiling path array comparative genomic hybridization (CGH), and we mapped the translocation breakpoints on chromosomes 6 and 7 by FISH. The clinical features of this patient-severe mental retardation, short stature, microcephaly and deafness-are in accordance with previously reported patients with 7q21 deletions. Chromosome band 7q21.3 harbors a locus for split hand/split foot malformation (SHFM1), and part of this locus, including the SHFM1 candidate genes SHFM1, DLX5, and DLX6, is deleted. The absence of limb abnormalities in this patient suggests either a location of the SHFM1 causing factor distal to this deletion, or reduced penetrance of haploinsufficiency of a SHFM1 factor within the deleted interval.
Recently, we showed that truncation of the X-linked cyclin-dependent kinase-like 5 (CDKL5/STK9) g... more Recently, we showed that truncation of the X-linked cyclin-dependent kinase-like 5 (CDKL5/STK9) gene caused mental retardation and severe neurological symptoms in two female patients. Here, we report that de novo missense mutations in CDKL5 are associated with a severe phenotype of early-onset infantile spasms and clinical features that overlap those of other neurodevelopmental disorders, such as Rett syndrome and Angelman syndrome. The mutations are located within the protein kinase domain and affect highly conserved amino acids; this strongly suggests that impaired CDKL5 catalytic activity plays an important role in the pathogenesis of this neurodevelopmental disorder. In view of the overlapping phenotypic spectrum of CDKL5 and MECP2 mutations, it is tempting to speculate that these two genes play a role in a common pathogenic process. In our recent study of two unrelated females with balanced X;autosome translocations, we showed that truncation of the cyclin-dependent kinase-like 5 (CDKL5/ STK9) gene causes a severe phenotype of early-onset infantile spasms, global developmental arrest, and profound mental retardation (Kalscheuer et al. 2003). The phenotypes in these patients are reminiscent of the neonatal-onset encephalopathy seen in several patients with a severe form of atypical Rett syndrome (RTT [MIM 312750]) (Schanen et al. 1998; Villard et al. 2000; Zeev et al. 2002). RTT is a progressive neurodevelopmental disorder that affects almost exclusively girls. The classic form of RTT is characterized by apparently normal development, followed by neurological developmental arrest and regression (Hagberg et al. 1983). The increase in cognitive and motor impairments may continue for
Despite twin and family studies having demonstrated a substantial heritability of individual diff... more Despite twin and family studies having demonstrated a substantial heritability of individual differences in intelligence, no genetic variants have been robustly associated with normal-range intelligence to date. This is largely ascribed to the high polygenicity of intelligence, i.e., to its being subject to the effects of a large number of genes of individually small effect. Intellectual disability, on the other hand, frequently involves large effects of single genetic mutations, many of which have been identified. The present paper aims to 1) introduce the reader to the current state of genetic intelligence research, including next-generation sequencing and the analysis of rare genetic variants, and 2) examine the possible effects of known disability genes on normal-range intelligence. The rationale for the latter rests on the fact that genetic variants affecting continuous, polygenic traits are often concentrated in the same areas of the genome as those underlying related monogenic phenotypes. Using an existing pool of known intellectual disability genes, we constructed a set of 168 candidate genes for normal-range intelligence, and tested their association with intelligence in 191 individuals (aged 5-18) sampled from the high and low ends of the IQ distribution. In particular, we 1) employed exon sequencing to examine the possible effects of rare genetic variants in the 168 genes, and 2) used polygenic prediction to examine the overall effect of common genetic variants in the candidate gene set in a larger sample (N = 2125, mean age 20.4, SD = 14.1). No significant association between the candidate gene set and intelligence was detected.
Pontocerebellar hypoplasia (PCH) is a heterogeneous group of rare recessive disorders with prenat... more Pontocerebellar hypoplasia (PCH) is a heterogeneous group of rare recessive disorders with prenatal onset, characterized by hypoplasia of pons and cerebellum. Mutations in a small number of genes have been reported to cause PCH, and the vast majority of PCH cases are explained by mutations in TSEN54, which encodes a subunit of the tRNA splicing endonuclease complex. Here we report three families with homozygous truncating mutations in TBC1D23 who display moderate to severe intellectual disability and microcephaly. MRI data from available affected subjects revealed PCH, small normally proportioned cerebellum, and corpus callosum anomalies. Furthermore, through in utero electroporation, we show that downregulation of TBC1D23 affects cortical neuron positioning. TBC1D23 is a member of the Tre2-Bub2-Cdc16 (TBC) domain-containing RAB-specific GTPase-activating proteins (TBC/RABGAPs). Members of this protein family negatively regulate RAB proteins and modulate the signaling between RABs a...
Massive parallel sequencing has revolutionized the search for pathogenic variants in the human ge... more Massive parallel sequencing has revolutionized the search for pathogenic variants in the human genome, but for routine diagnosis, re-sequencing of the complete human genome in a large cohort of patients is still far too expensive. Recently, novel genome partitioning methods have been developed that allow to target re-sequencing to specific genomic compartments, but practical experience with these methods is still limited. In this study, we have combined a novel droplet-based multiplex PCR method and next generation sequencing to screen patients with X-linked mental retardation (XLMR) for mutations in 86 previously identified XLMR genes. In total, affected males from 24 large XLMR families were analyzed, including three in whom the mutations were already known. Amplicons corresponding to functionally relevant regions of these genes were sequenced on an Illumina/Solexa Genome Analyzer II platform. Highly specific and uniform enrichment was achieved: on average, 67.9% unambiguously mapped reads were derived from amplicons, and for 88.5% of the targeted bases, the sequencing depth was sufficient to reliably detect variations. Potentially diseasecausing sequence variants were identified in 10 out of 24 patients, including the three mutations that were already known, and all of these could be confirmed by Sanger sequencing. The robust performance of this approach demonstrates the general utility of droplet-based multiplex PCR for parallel mutation screening in hundreds of genes, which is a prerequisite for the diagnosis of mental retardation and other disorders that may be due to defects of a wide variety of genes.
Localization of the gene for X-Iinked Alport's syndrome. X-chromosomal DNA probes defining variou... more Localization of the gene for X-Iinked Alport's syndrome. X-chromosomal DNA probes defining various polymorphic DNA markers were used to study genetic linkage in three families with Alport's syndrome. With the DXS17 marker, only a single cross-over was observed in 26 informative meioses, and evidence for linkage was also obtained with the DXS 11 marker. These data localize the gene for the X-linked form of Alport's syndrome to the middle of the long arm of the X chromosome. Alport's syndrome is characterized by hereditary glomerulo
A balanced translocation was recently identified in a German psoriasis patient. One of the breakp... more A balanced translocation was recently identified in a German psoriasis patient. One of the breakpoints was mapped immediately upstream of the microsomal glutathione S-transferase 2 (MGST2) gene, suggesting it as a candidate gene. Here, we report the identification of a novel non-synonymous mutation in MGST2 by a comprehensive sequence analysis of MGST2's coding region in Chinese psoriasis samples. We demonstrate that this mutation co-segregated with the disease phenotype within a Chinese family affected with psoriasis vulgaris and is predicted to have an impact on the normal function of MGST2 protein. However, the mutation was absent in 551 additional cases and 384 healthy Chinese controls. While requiring independent confirmation, our results suggest that this rare mutation could play a causal role in a small subset of psoriasis individuals.
A family with myoclonus epilepsy has been described previously as suffering from an X-linked diso... more A family with myoclonus epilepsy has been described previously as suffering from an X-linked disorder, because at least four males were affected, and only mild and variable symptoms were seen in some female carriers. In this family, we have now identified a mitochondrial A-~G (8344) heteroplasmic point mutation. This point mutation has been described in families with maternally inherited myoclonus epilepsy and ragged red fibers. The degree of severity of the disorder in the different family members was reflected in the relative quantity of mutated mitochondrial DNA. It is concluded that the mode of inheritance in this family is not X-linked but maternal.
In 16 families with myotonic dystrophy (DM) a novel approach based on use of allele-specific olig... more In 16 families with myotonic dystrophy (DM) a novel approach based on use of allele-specific oligonucleotides has been employed to study the linkage relationship between the apolipoprotein E (APOE) gene and DM. Synthetic oligonucleotides, designed to discriminate between APOE alleles ~3 and ~4, enabled us to distinguish heterozygous carriers in a hybridization assay. In a subset of families, the relevant segment of the APOE gene was enzymatically amplified to increase the sensitivity of the method. For DM and APOE, a maximum lod score (Zmax of 7.47 was obtained at a recombination frequency (0) of 0.047 (male 0 = female 0). No recombination (maximum lod score of 5.61 at 0 = 0.0) was found between APOE and the apolipoprotein CII (APOC2) gene. These results suggest that, in addition to APOC2, APOE is a useful marker for presymptomatic DM diagnosis.
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Papers by Hilger Ropers