Genetic heterogeneity of dominantly inherited olivopontocerebellar atrophy (OPCA) in the Japanese: Linkage study of two pedigrees and evidence for the disease locus on chromosome 12q (SCA2)

Summary We did a linkage study of 2 multigenerational pedigrees with dominant olivopontocerebellar atrophy (OPCA) other than SCA1, with chromosome 12q microsatellites. Multipoint linkage analysis led to the conclusion that the disease locus locates within the 6.2 cM interval between IGF1 and D12S84/D12S105. This result coincides with that of Cuban ataxia pedigrees designated as SCA2. Our study provides genetic evidence that dominant OPCA in the Japanese consists of at least two genetically different disorders: SCA1 and SCA2.     

谷胱甘肽S—转移酶异质性研究

本文以不同状态的大鼠肝细胞为对象,采用生化和病理学方法研究了谷胱甘肽S-转移酶(GST)的异质性。根据GST同工酶酶谱分忻、GST活性改变状况和GST同工酶表达活性的改变等结果,表明GST无论在正常状态或病理状态下均具有显著的异质性。     

Application of the lod score method to detection of linkage between HLA and juvenile insulin-dependent diabetes

The lod score method has been applied to 28 informative families with at least one child suffering from juvenile insulin-dependent diabetes (JIDD), assuming autosomal recessive inheritance, for detection of linkage between HLA and a susceptibility locus for this disease. These 28 families were pooled with 21 other families from the literature. The maximum lod scores were obtained for recombination fractions from 4 to 16 %, according to the level of penetrance (10 to 90 %). These high estimates of the recombination fraction are not in agreement with the hypothesis that the association between JIDD and specific HLA haplotypes is due to a simple linkage disequilibrium between the HLA region and a susceptibility locus for JIDD.     

Corneal dermoids and short stature in brother and sister—A new syndrome?

We describe 2 sibs; brother and sister, with corneal dermoids and proportionately short stature. It is suggested that this is an autosomal recessive condition.     

Autosomal dominant lamellar ichthyosis: a new skin disorder

Lamellar ichthyosis (nonbullous congenital ichthyosis) has been explained as an autosomal recessive trait. We have found an autosomal dominant type of this disorder. Four patients, belonging to three consecutive generations of a family, were affected from birth. The disorder was characterized by large, dark brown scales covering the entire body including flexural folds, palms and soles. X-linked recessive ichthyosis was excluded by clinical appearance, pattern of transmission and normal electrophoretic mobility of beta-lipoproteins. Autosomal dominant ichthyosis vulgaris and bullous ichthyosiform erythroderma were excluded by the histological and ultrastructural features. In the absence of a positive family history, this skin disorder would have been taken for autosomal recessive lamellar ichthyosis. This new autosomal dominant type of ichthyosis should be considered for differential diagnosis, when genetic counselling is given in a sporadic case of lamellar ichthyosis.     

Quantitative-trait-locus Mapping in the Presence of Locus Heterogeneity

Locus heterogeneity is a concern for quantitative trait locus mapping where phenotypes are likely to be influenced by more than one gene. We introduce a model which generalizes the locus heterogeneity model of Smith (1961) from dichotomous traits to quantitative traits and consider some test statistics for this model. The type I error rates and the power of these statistics are assessed through simulation studies. These statistics are applied to a linkage study of asthma genes.     

Duchenne-like muscular dystrophy in two sisters with normal karyotypes: evidence for autosomal recessive inheritance

Two sisters, products of a consanguineous marriage (with a total of 12 children) showed muscle weakness at ages 7 and 6 yrs, respectively. The symptoms progressed rapidly and the patients were confined to wheelchairs at ages of 12 and 11 yrs, respectively. They had mild facial weakness and pseudohypertrophy of the calves, but neither cardiomyopathy nor mental retardation. Serum CK activities exceeded upper normal limit by 70 to 85-fold. Muscle biopsies were compatible with muscular dystrophy. Both girls had a normal karyotype. The healthy mother had mild CK elevations in two out of three occasions, but the muscle biopsy was normal. Three out of the six unaffected sibs had mild CK elevations. The findings support the concept of severe progressive muscular dystrophy with autosomal recessive inheritance. The condition is clinically indistinguishable from Duchenne muscular dystrophy.     

Familial spastic paraparesis: Evaluation of locus heterogeneity,anticipation, and haplotype mapping of the SPG4 locus on the short arm of chromosome 2

Familial spastic paraparesis (SPG) is a clinically and genetically heterogeneous group of disorders. At least three loci have been implicated in autosomal dominant pure SPG and mutations in either of two loci may cause the X-linked form. Although the penetrance is high for all forms by age 60, there is wide variation in clinical characteristics, including age of onset. Two-point and multi-point linkage analyses in nine families provided supportive evidence that the most common form of SPG is linked to chromosome 2 (SPG4). Haplotype analysis localized the critical region to a 6 cM interval between D2S392 and D2S367. By haplotype analysis, the disease in at least one family does not appear to be linked to any of the presently known SPG loci, suggesting that there is at least one additional SPG gene. Evaluation of ages of onset in 11 families gave suggestive evidence for anticipation with mean age of onset in parents (41.3 years) being older than mean age of onset in children (26.9 years; P < 0.005). Am. J. Med. Genet. 74:26–36, 1997. © 1997 Wiley-Liss, Inc.     

Advanced glycation end products (AGEs) and their receptor (RAGE) induce apoptosis of periodontal ligament fibroblasts

Diabetics have an increased prevalence of periodontitis, and diabetes is one of thecausative factors of severe periodontitis. Apoptosis is thought to be involved inthis pathogenic relationship. The aim of this study was to investigate apoptosis inhuman periodontal ligament (PDL) fibroblasts induced by advanced glycation endproducts (AGEs) and their receptor (RAGE). We examined the roles of apoptosis, AGEs,and RAGE during periodontitis in diabetes mellitus using cultured PDL fibroblaststhat were treated by AGE-modified bovine serum albumin (AGE-BSA), bovine serumalbumin (BSA) alone, or given no treatment (control). Microscopy and real-timequantitative PCR indicated that PDL fibroblasts treated with AGE-BSA were deformedand expressed higher levels of RAGE and caspase 3. Cell viability assays and flowcytometry indicated that AGE-BSA reduced cell viability (69.80±5.50%, P<0.01) andincreased apoptosis (11.31±1.73%, P<0.05). Hoechst 33258 staining andterminal-deoxynucleotidyl transferase-mediated nick-end labeling revealed thatAGE-BSA significantly increased apoptosis of PDL fibroblasts. The results showed thatthe changes in PDL fibroblasts induced by AGE-BSA may explain how AGE-RAGEparticipates in and exacerbates periodontium destruction.     

Power to detect linkage with heterogeneity in samples of small nuclear families

Computer simulation methods were used to investigate the power of genetically homogeneous or heterogeneous samples of nuclear families to detect linkage of a rare dominant disease allele to flanking DNA markers (threepoint analysis, admixture text). Phase was assumed to be unknown (no grandparents available), and unaffected siblings were not considered. A sample of 95 families with an ill parent and two ill offspring, or 45 families with three ill offspring, demonstrated 90% power to detect a lod score of 3.0 when 50% of families were assumed to be segregating for a disease allele located midway between two DNA markers (PIC = .70) that were .05 M apart. When the proportion of linked families (α) = .25, 90% power required 380 and 160 families, respectively. For α < .25, sample size requirements become prohibitive. Issues are reviewed concerning the use of the admixture test in the case of more complex disease models. Screening of the genome with adequate sample sizes for low values of α is likely to require multiple large collaborative efforts. © 1993 Wiley-Liss, Inc.     

Genetic heterogeneity of diabetes and HLA

Histocompatibility (HLA) antigens and genotypes B, D and DR were studied in a large sample of Caucasian insulin dependent diabetic (IDD) probands. The associations between IDD and B8, B15, Dw3, Dw4, DR3, and DR4 were measured by relative risks (RR) and delta values (δ). Both the homozygotes (B8/8: RR 10, B 15/15: RR 7, DR3/3: RR32, DR4/4: RR34) and the heterozygotes (B8/15: RR 11, DR3/4: RR 46, Dw3/4: RR 22) for the high-risk antigens showed highly significant elevation of the relative risks, yet there were no statistically significant differences between the homo- and the heterozygotes. The δ measurements supported the RR results. RR and δ were found significantly decreased for B7, Dw2, and DR2. There were no relationships observed between age at diagnosis or family history and HLA. Although we were unable to demonstrate a statistically significant difference between the RR for the high-risk antigens heterozygote vs. the high-risk antigen homozygotes, our study like many others shows that the RR is higher for the heterozygotes. Thus our data are compatible with genetic heterogeneity of IDD.     

Behavioral evidence of thermal hyperalgesia in non-obese diabetic mice with and without insulin-dependent diabetes

The non-obese diabetic (NOD) mouse, a model of Type 1 diabetes in humans, has proven useful for the study of genetic, immunologic and epidemiologic aspects of inherited diabetes. Behavioral evidence of hyperalgesia may also be present in the NOD mouse but has not been described. This study examined NOD mice with (NOD+) and without (NOD−) insulin-dependent diabetes, and control strain (ILI) mice for evidence of hyperalgesia to a noxious thermal stimulus. Interestingly, both NOD+ and NOD− mice showed reduced mean hindpaw withdrawal latencies when compared with non-diabetic ILI mice. NOD+ and NOD− mice were also abnormal in their general appearance, activity level, posture, gait and muscle bulk when compared with ILI mice. These findings raise the possibility that hyperalgesia in insulin-dependent NOD mice, or insulin-dependent humans with Type 1 diabetes, may be independent of diabetes and due to a primary disturbance within sensory pathways.     

Genetic Heterogeneity of Mycoplasma hominis Clinical Isolates Detected during Observation of Patients with Recurrent Urogenital Inflammation

A rapid reproducible effective method for molecular typing of Mycoplasma hominis strains based on random amplified polymorphic DNA (RAPD) technique was developed. RAPD detected genetic heterogeneity of genomes of Mycoplasma hominis clinical isolates and showed changes in the genomes of Mycoplasma hominis clinical isolates from patients with chronic infection.     

Childhood manifestation of autosomal dominant polycystic kidney disease: no evidence for genetic heterogeneity

Autosomal dominant polycystic kidney disease (ADPKD) usually becomes symptomatic between the third and fifth decades. We studied ten families segregating for ADPKD in which children were observed with typical manifestations of the disease at birth or in early childhood. In these families, linkage analysis was carried out with a cloned DNA sequence from the alphaglobin locus known to be closely linked to the disease gene in adult onset ADPKD. In the families studied here, close linkage ( θ _max= 0.09 at Z_max= 2.32) was also observed between the marker and disease loci. These results provide no evidence for genetic heterogeneity of ADPKD in families with early and adult onset.     

肿瘤组织力学异质性与肿瘤细胞的上皮-间质转化

在肿瘤生长过程中,随着癌细胞的增殖扩张、癌组织胞外基质的重建、周围组织的约束及癌组织间隙液的流动等,肿瘤组织内形成了特殊的应力环境。肿瘤组织不同区域的力学环境和力学特征存在显著差异,即肿瘤组织的力学异质性。研究发现,肿瘤组织侵袭前沿区域的力学特征更加显著和复杂。特别地,肿瘤细胞的上皮-间质转化（epithelial-mesenchymal transition,EMT）也偏好集中于该区域,侵袭前沿产生的机械应力可通过TWIST1、TGF-β、WNT等力信号转导途径诱导侵袭前沿肿瘤细胞的EMT,促成肿瘤细胞的侵袭性表型。从肿瘤生物力学角度出发,对肿瘤组织的力学异质性、肿瘤细胞的EMT以及两者的关系加以综述,为力学微环境靶向的肿瘤治疗提供理论依据。     

Genetic mapping of loci for X-linked retinitis pigmentosa

Linkage analysis was performed in three Swedish families segregating for X-linked retinitis pigmentosa (XLRP), using five polymorphic DNA markers assigned to Xp. Individual recombination events were analyzed and two- and five-point linkage analysis was undertaken. In one family, a XLRP locus was mapped to the same position as OTC corresponding to RP3. In two families, a disease locus linked to OTC was excluded. In one family, recombination events indicate a locus for XLRP outside the interval (DXS84-OTC-DXS255-DXS14), most likely on the centromeric side of DXS14.     

柯萨奇B4病毒诱导的实验性糖尿病小鼠血清一氧化氮浓度的变化

目的:观察CB₄V诱导的实验性糖尿病小鼠血清NO浓度的变化以及在不同时期产生的IL-1水平。方法:建立CB₄V诱导的实验性糖尿病小鼠模型,分别在病毒感染后72h、1周、3周、6周、8周,用硝酸还原酶法测定血清NO^-₂/NO^-₃含量,同时测定经LPS诱导的巨噬细胞产生的IL-1水平。结果:(1)血清NO^-₂/NO^-₃浓度变化:对照组各时期血清NO^-₂/NO^-₃浓度无显著差异,模型组小鼠血清NO^-₂/NO^-₃浓度在CB₄V感染72h后显著增高(P＜0.01),在感染后1周达到高峰,6-8周时接近正常水平。(2)IL-1水平的测定:在CB₄V感染后72h,IL-1水平明显高于对照组(P＜0.01),1周达到高峰(P＜0.01),6周接近正常水平。在各时期NO^-₂/NO^-₃与IL-1均呈高度正相关。结论:NO可能参与CB₄V诱导的IDDM发生发展过程。     

Impact of complex genetic conditions on public health

Complex genetic diseases are often common: in most common diseases liability is influenced by genetic variation. The ways in which this variation is analyzed are discussed using diabetes, affective disorders and schizophrenia as examples. Molecular biology has opened new paths for a more incisive analysis of genetic heterogeneity and biological mechanisms. However, important population genetic aspects such as mutation and selection are largely unexplored. Therefore, predictions regarding possible increases or decreases in frequencies of susceptibility genes are hardly feasible. In many cases, however, the public health impact of such diseases can be alleviated and the quality of life of the individual can be improved, by appropriate adaptation of relevant environmental factors.