Exclusion of linkage to 14q23-24 in a family with Holt-Oram syndrome

Holt-Oram syndrome is an autosomal dominant disorder with congenital heart defects and skeletal malformations of the upper extremities. A patient with a deletion of 14q23-24 and Holt-Oram syndrome has been described. In this report, however, genetic linkage to the 14q23-24 region is excluded in a multigeneration family with five available individuals affected with Holt-Oram syndrome. Familial Holt-Oram syndrome might be different from the syndrome with the 14q23-24 deletion.     

Mapping of a disease locus for familial rapidly progressive frontotemporal dementia to chromosome 17q12-21

Familial frontotemporal dementia (FTD) is a complex disorder with lack of distinctive histopathological markers found in other types of dementia. Most of the linkage reports from FTD families map the disease loci to chromosome 17q21-22. However, FTD is genetically heterogeneous, as linkage also has been reported to chromosome 3. In the present study, we investigated the genetics of a Swedish family with an early-onset type of rapidly progressive FTD, associated with muscular rigidity and akinetic movements. Neuropathological features such as severe frontal lobe degeneration, spongy changes, and gliosis were present in affected family members. We here report probable linkage to chromosome 17q12-21 with a maximum two-point lod score of 2.76 at θ = 0 for marker D17S806, and a peak multipoint lod score of 2.86 for the same marker. Linkage to chromosome 3 was excluded, as two-point lod scores of −2.79, and −2.27 at θ = 0.01 for markers D3S1603 and D3S1552, respectively, were obtained. Sequencing of the translated exons of a strong candidate gene in the linked region of chromosome 17, the tau gene, failed to identify any mutations segregating with the disease. Am. J. Med. Genet. 74:380–385, 1997. © 1997 Wiley-Liss, Inc.     

Deletion 4q21/4q22 syndrome: Two patients with de novo 4q21.3q23 and 4q13.2q23 deletions

We report on 2 patients with de novo proximal interstitial deletions of the long arm of chromosome 4: in one the deletion resulted in monosomy (4)(q21.3q23), in the other it produced monosomy (4)(q13.2q23). Review of 9 cases of deletions involving the 4q21/4q22 region reported previously detected a characteristic phenotype in S patients. This phenotype was present in our patients. We conclude that the deletion in the 4q21/4q22 region results in a specific clinical syndrome associated with central nervous system overgrowth that may be a result of anomalous imprinting in the 4q21/4q22 region. Am. J. Med. Genet. 69:400–405, 1997. © 1997 Wiley-Liss, Inc.     

Hippocampal neuronal subpopulations are differentially affected in double transgenic mice overexpressing frontotemporal dementia and parkinsonism linked to chromosome 17 tau and glycogen synthase kinase-3beta

Glycogen synthase kinase-3beta (GSK-3beta) has been proposed as the main kinase able to phosphorylate tau aberrantly in Alzheimer's disease and in related tauopathies. We have previously generated a double transgenic mouse line overexpressing the enzyme GSK-3beta and tau protein carrying a triple frontotemporal dementia and parkinsonism linked to chromosome 17 mutation whose expression patterns overlap in CA1 (pyramidal neurons) and dentate gyrus (granular neurons). Here, we have used this transgenic model to analyze how axonal and somatodendritic neuronal compartments are affected in the hippocampus. Our data demonstrate that neuronal subpopulations respond differentially to increased GSK-3 activity. Thus, dentate gyrus granular neurons undergo apoptotic death with subsequent degeneration of the mossy fibers, while CA1 pyramidal neurons accumulate hyperphosphorylated tau both in the axonal and in the somatodendritic compartments. These studies also allow us to propose a model of spreading of pathology through the hippocampus as a consequence of GSK-3 and tau dysregulation.     

Decreased oligodendrocyte nuclear diameter in Alzheimer's disease and lewy body dementia

To better understand the pathogenesis of dementia, it is important to understand histopathologic changes in neurodegenerative diseases because they might highlight key aspects of the degenerative process. In this study, the nuclear diameter of neurons and oligodendrocytes in selected temporal lobe areas were determined in autopsy tissue sections from patients with Alzheimer's disease (AD), Lewy body dementia (LBD) and controls. Our morphometric studies targeted neurons in the CA4 region of the pyramidal cell layer of the hippocampus, neurons in the granular layer of the dentate gyrus and oligodendrocytes in parahippocampal white matter. Mean neuronal nuclear diameters were not different among the studied groups. However, our studies revealed a statistically significant reduction of mean oligodendrocyte nuclear diameter in AD and LBD relative to controls. The reduction of the mean nucleus diameter of oligodendrocytes in LBD was independent of the presence of associated AD pathology in LBD. These findings for the first time identify decreased oligodendrocyte nucleus diameter as a morphologic feature of AD and LBD and may lead to a better understanding of the role of oligodendrocytes in AD and LBD pathogenesis.     

CD28/CTLA4 gene region on chromosome 2q33 confers genetic susceptibility to celiac disease. A linkage and family-based association study

Celiac disease (CD) is a common small intestinal injury caused by sensitivity to gliadin in genetically-predisposed individuals. The only susceptibility locus established is the HLA-DQ. We tested whether the chromosomal region of the CD28/CTLA4 genes on 2q33 is linked to CD. These genes encode receptors regulating the T-lymphocyte activation. Recently, this gene region was reported to be linked to the susceptibility to many autoimmune diseases, including insulin-dependent diabetes (IDDM12locus). It is thus an obvious candidate locus also for CD, since the intestinal injury is mediated by the immune system. Genetic linkage between seven marker loci in this gene region and CD was studied in 69 Finnish families. In the multipoint linkage analysis, the highest non-pararametric linkage score (NPL) was 1.75 (P=0.04) for D2S116, suggesting weak linkage for this candidate locus. To evaluate this finding, an additional 31 families were typed for all markers. In the combined set of 100 families the NPL score for marker D2S116 was 2.55 (P=0.006) and for other markers 1.90-2.47 (P=0.029-0.007), supporting genuine linkage at this region. Significantly, locus D2S116 also showed a clear allelic association in these 100 families (P=0.0001). The transmission/disequilibrium test (TDT) for locus D2S116 gave preliminary evidence for preferential maternal non-transmission of allele *136 to patients (TDTmax=8.3; P<0.05). No paternal deviation was found suggesting that the effect of the locus might be mediated by a sex-dependent factor protective against CD. Our results indicate that the CD28/CTLA4 gene region can contain a novel susceptibility locus for CD and support the hypothesis that CD has an immune system-mediated component. Like the HLA, the CD28/CTLA4 genes appear to be associated with genetic susceptibility to various autoimmune diseases.     

No evidence of linkage to chromosome 9q21-22 in a Swedish family with frontotemporal dementia and amyotrophic lateral sclerosis

Frontotemporal dementia (FTD) is a neurodegenerative disorder, sometimes occurring together with amyotrophic lateral sclerosis (ALS) within the same family. Recently, a region on chromosome 9q21–22 was reported to harbour a locus that may participate in both disorders [Hosler, B.A., et al., JAMA., 284 (2000) 1664-1669]. In the present study, a Swedish pedigree with both ALS and FTD segregating in the family was investigated by linkage analysis with five markers on chromosome 9q21–22. The pedigree included 17 individuals in two generations, with five affected cases available for analysis. As two-point logarithm of odds scores close to zero were obtained for all markers tested, the region on chromosome 9q21–22 is suggested to be excluded as candidate region in this Swedish FTD/ALS family. Our conclusion is therefore that additional loci involved in these two disorders must be operating.     

Study of the genetic variability in a Parkinson's Disease gene: EIF4G1

Chartier-Harlin and colleagues [2] recently reported mutations in the eukaryotic translation initiation factor 4-gamma (EIF4G1) gene in families with parkinsonism. Large-scale screening found two mutations (p.R1205H and p.A502V) only in affected individuals, although their relative frequency was very low. The aim of this study was to investigate EIF4G1 parkinsonism-related variants in two separate cohorts and study coding variability across the gene. We first screened a series of familial Parkinson's Disease (PD) patients in an attempt to confirm previous results by showing segregation. Then, to determine the extent of coding variation in the gene, we first screened a cohort of sub-Saharan African individuals from the Centre d'Etude du Polymorphisme Humain - Human Genome Diversity Cell Line Panel (HGDP) [1] and then analyzed data from 5350 individuals National Heart, Lung, and Blood Institute (NHLBI) exome sequencing project. We failed to identify any PD-related mutations in the familial samples. Conversely we found the p.A502V variant in the NHLBI population. We observed a high number of coding polymorphism in the exons where the two PD variants have been previously reported. We conclude that either EIF4G1 variants are an extremely rare cause of familial PD in Caucasian cohorts, or that A502V is in fact a rare benign variant not involved in PD aetiology. Our data also suggests that the protein can tolerate some extent of variability particularly at this point of the gene.     

Analysis of the PINK1 gene in a cohort of patients with sporadic early-onset parkinsonism in Taiwan

Mutations in the PINK1 gene have been shown to cause autosomal recessive Parkinson's disease (PD) and/or early onset sporadic PD in Italy, Spain, North America, Ireland, and Asia. However, there are limited data on PINK1 mutations in sporadic early onset Asian PD patients. To determine the prevalence of PINK1 mutation in Taiwanese population, we conducted genetic analysis of PINK1 mutation in 73 early onset sporadic PD and 94 normal control subjects. We only identified a novel single heterozygous mutation R 407Q mutation in exon 6 of this gene in one patient at the age onset of 54. Overall, these data indicate that PINK1 mutations are rare in our population. Based on our results, unless common mutational hotspots are identified, routine testing for this mutation at least in our population may not be cost-effective.     

Localization of a novel gene for nonsyndromic hearing loss (DFNB17) to chromosome region 7q31

Autosomal recessive nonsyndromic hearing loss (ARNSHL) is the most common form of hereditary hearing impairment (HHI). To date, 16 different loci have been reported, making ARNSHL an extremely heterogeneous disorder. One of these loci, DFNB4, was mapped to a 5-cM interval of 7q31 in a large Middle-Eastern Druze family. This interval also includes the gene for Pendred syndrome. We report on three new families with HHI from the Madras region of southern India that demonstrate linkage to 7q. Their pedigrees are compatible with autosomal recessive inheritance. Furthermore, the largest family identifies a novel locus (DFNB17) telomeric to the DFNB4 and Pendred intervals. A 3-cM region of homozygosity by descent between markers D7S486 and D7S2529 is present in all affected individuals in this family and generates a multipoint LOD score of 4.24. The two other families map to the previously reported DFNB4 region but have insufficient power to attain significant LOD scores. However, mutations in the Pendred syndrome gene are present in one of these families. Am. J. Med. Genet. 78:107–113, 1998. © 1998 Wiley-Liss, Inc.     

Dysmorphic features and learning disability in an adult male with pure partial trisomy 17q24‐q25 due to a terminal duplication

We describe an adult male with severe learning disability, epilepsy, and dysmorphic features. Cytogenetic studies demonstrated a terminal duplication of the long arm of chromosome 17, resulting in partial trisomy 17q24‐q25. Our patient shows some of the characteristic features of the distal 17q phenotype, but in addition has more unusual features such as epilepsy, sensorineural hearing loss, and long fingers and overlapping toes. We suggest that these features occur with terminal duplications of 17q. © 2002 Wiley‐Liss, Inc.     

A 2.1 Mb deletion adjacent but distal to a 14q21q23 paracentric inversion in a family with spherocytosis and severe learning difficulties

A familial q21.1q23.2-inversion on chromosome 14 that co-segregated with spherocytosis and learning difficulties or mild mental retardation was extensively investigated by bacterial artificial chromosome fluorescence in situ hybridization and array-comparative genomic hybridization. As expected, a deletion of the beta-spectrin gene SPTB, a known cause of spherocytosis, was found. More unexpectedly, this deletion was approximately 1.6 Mb distal to the 14q23.2-inversion breakpoint. The deletion spanned approximately 2.1 Mb and contained 15 annotated genes in addition to SPTB, among them PLEKHG3, a guanide nucleotide exchange factor for Rho GTPases. This gene is highly expressed in the brain and our best candidate for causing the mild mental retardation. The case illustrates that inversions can be associated with microdeletions close to but not including one of the inversion breakpoints.     

Association of interleukin-17A and -17F gene single-nucleotide polymorphisms with autoimmune thyroid diseases

Th17 lymphocyte and its relative cytokines have been shown to play an important role in autoimmune thyroid diseases (AITD). The aim of this study was to investigate the association between IL-17A and IL-17F gene polymorphisms and two main types of AITD, Graves' disease (GD) and Hashimoto's thyroiditis (HT). Whole blood specimens and clinical data were collected from 508 AITD patients (326 with GD and 182 with HT) and 224 age- and gender-matched healthy controls, respectively. IL-17A (rs2275913, rs8193037, rs3819025) polymorphism was determined using DNA sequencing method and IL-17F/rs763780 polymorphism was assayed by polymerase chain reaction-restriction fragment length polymorphism (PCR -RFLP). The results indicated that the frequencies of IL-17F/rs763780 genotypes in patients with GD and HT differed significantly from their controls (P = 0.013 and P = 0.005, respectively); the G allele frequencies were also significantly higher in the patient groups than the control groups (P = 0.002 and 0.001, respectively). For IL-17A/rs2275913 and rs8193037 SNP, no significant difference was observed in patients with either GD or HT compared to the control groups (P>0.05). Interestingly, for rs3819025, the frequency of A allele was lower in patients with GD than controls (P = 0.011). The frequencies of haplotype AGGG and GGGG in patients with GD and HT were significantly higher than in controls (P = 0.012, P = 0.019, P = 0.017 and P = 0.029, respectively). In conclusion, the results indicate that IL-17F/rs763780 polymorphisms may affect the susceptibility to AITD, and IL-17A/rs3819025 SNP is likely a protective factor to GD in the Chinese population.     

Support for linkage of familial combined hyperlipidemia to chromosome 1q21-q23 in Chinese and German families

We examined familial combined hyperlipidemia (FCHL) families from nonisolated regions in Germany and China to see if we could corroborate support for a chromosome 1q FCHL locus in more general populations. We recruited 24 German families with 137 members, 92 of whom met the criteria of affected in terms of the low density lipoprotein (LDL) and triglyceride levels in excess of the 90th percentile for age and gender. In China, we recruited 12 families with a total of 81 members. All affected persons had total cholesterol concentrations >240 mg/dl and triglyceride concentrations >250 mg/dl. We examined the markers APOA2, D1S1677, D1S104, D1S194, D1S426, and D1S196. Two-point linkage analysis allowing for heterogeneity gave a maximum linkage of disorder score (HLOD) of 2.60 right over D1S194, estimating the proportion of linked families at 36%. This marker is adjacent to D1S104. The evidence for linkage was roughly the same both in the German (HLOD 1.40) and Chinese families (HLOD 1.52). Marker D1S194 is close to the retinoid X receptor (RXR) gene locus, which was found to be linked to triglyceride levels in an earlier twin study from our laboratory. We interpret our observations as encouraging support for the recent findings indicating the presence of a gene for FCHL on chromosome 1q. Furthermore, since DIS194 is adjacent to the gene for the RXR, we suggest that RXR is an attractive candidate for involvement in FCHL.     

Exclusion of type II and type VI procollagen gene mutations in a five-generation family with multiple epiphyseal dysplasia

We have studied a family with an autosomal dominant form of multiple epiphyseal dysplasia (MED) inherited through at least 5 generations. Bilateral deformity of the hips with subsequent degenerative arthritis was the most common and most severe change observed in the affected relatives. Abnormalities of the knees, ankles, and shoulders were also noted in some affected individuals. Radiological examination showed changes in affected joints consistent with epiphyseal dysplasia. In early stages, the articular surfaces appeared flattened or irregular in shape. In advanced stages, epiphyseal fragmentation, joint surface erosion, and extensive remodeling were observed. The abnormalities of the epiphyses suggested that the primary defect might be in a structural component of the epiphyseal cartilage matrix. The gene encoding type II collagen (COL2A1) was tested for genetic linkage to MED in this family by restriction fragment length polymorphism (RFLP) analysis. Recombination between COL2A1 and MED was observed, ruling out COL2A1 as the site of the mutation. The genes encoding the 3 chains of type VI collagen were also excluded on the basis of discordant inheritance. The disease in this family is therefore not the result of mutations in the genes encoding type II or type VI collagen. © 1993 Wiley-Liss, Inc.     

Assignment of PGL3 to chromosome 1 (q21‐q23) in a family with autosomal dominant non‐chromaffin paraganglioma

We performed a whole genome scan in a family with maternally transmitted paraganglioma (PGL3). The family included five patients with histologically proven paraganglioma and one patient with imaging findings consistent with a paraganglioma. In addition, there were 33 clinically unaffected family members. Of these eight could be examined by magnetic resonance imaging. Our investigations indicate that PGL3 is located in 1q21‐q23 for several reasons: 1) two‐point linkage analysis yielded the highest LOD score of 2.25 at 1q21‐q23 (marker D1S2675); 2) haplotype analysis was most consistent for 1q21‐q23 markers; and 3) the locus was excluded from more than 97% of the genome using a total of 381 highly polymorphic markers. © 2001 Wiley‐Liss, Inc.