Genetic marker family studies in familial Mediterranean fever (FMF) in Armenians

Familial Mediterranean fever is an autosomal recessive disease manifested by recurrent short episodes of fever associated with polyserositis. It is common in a variety of Mediterranean and near Eastern populations. The biochemical defect is unknown, and there have been few studies of genetic marker associations or linkage with the disease. We have screened blood samples from members of 14 nuclear Armenian families, the population with the highest known gene frequency, for 19 different polymorphic phenotypic genetic markers. These 14 families included 31 affected and 43 unaffected family members. No association was found with any of the markers studied. Linkage could be excluded at the distance of 0-15% recombination with 14 markers. Linkage could not be excluded with 5 other markers. These results exclude the FMF gene from those portions of the human gene map that are at least 0.5% recombination distance from these 14 genetic markers, and represent the first comprehensive step in the eventual localization and isolation of the FMF gene.     

Gene mapping studies with the syndrome of autism

The UCLA Registry for Genetic Studies of Autism had collected data on 308 families by February 1, 1983. A subsample of 46 families withat least two affected children was analyzed for evidence of a Mendelian mode of inheritance. The data were consistent with an autosomal recessive mode of inheritance (Ritvo, E. R., Spence, M. A., Freeman, B. J. Mason-Brothers, A., Mo. A., and Marazita, M. L., 1985, American Journal of Psychiatry, in press). Thirty-four of these families were subjected to gene linkage analyses with 30 standard phenotypic gene markers. There is no evidence of linkage between the purported autism locus and HLA, either from analysis of HLA haplotype sharing or fromlod scores. In addition, close linkage with autism, i.e., 5% recombination, could be excluded for 19 of the other autosomal genetic markers. The largest positivelod score, 1.04, was with haptoglobin (HP), at recombination frequencies of 10% in males and 50% in females. Normal C-and Q-banded chromosome polymorphisms were evaluated for association with autism and as additional linkage markers.This work was supported in part by the Max and Lottie Dresher Research Fund, the Bennin Fund, Grants MH 31274, MCT 927, and MH 30897 from the NIMH and Grants HD 05615 and HD 04612 from the NIH and with the cooperation of the National Society for Children and Adults with Autism (NSAC), Washington, D.C.     

A rare case of nasal Schneiderian (inverted) papilloma associated with basaloid squamous cell carcinoma

Sinonasal inverted papilloma (IP) is a benign, locally aggressive epithelial neoplasm. In less than 9% of cases it is associated with malignancies, typically conventional squamous cell carcinomas (SCC), while other histological variants have been less frequently reported. We describe the third case of basaloid squamous cell carcinoma (BSCC) arising in nasal IP.An 81-year-old female patient presented with a pinkish irregular lesion on the nasal septum. Biopsy was consistent with IP and carcinoma in situ. Two surgical procedures were needed to obtain radical excision. Histology on the surgical specimen revealed BSCC. Seven months after surgery, there was no evidence of disease recurrence.Although IP is more frequently associated with conventional SCC, other malignancies should be considered. The histological differential diagnosis should be supported by immunohistochemistry. The generally-recommended treatment for sinonasal BSCC is complete surgical resection, although this may be a problem in multifocal distributions, as in the present case.     

Spondyloepiphyseal dysplasia in a cape town family: Linkage with the gene for type II collagen (COL2A1)

A moderately severe form of autosomal dominant (AD) spondyloepiphyseal dysplasia (SED) has been documented in 14 individuals in 3 generations of a family in Cape Town, South Africa. Affected persons had a short trunk; radiographic investigations indicated that skeletal involvement was worst in the hips and spine. Linkage studies with restriction fragment length polymorphisms (RFLPs) associated with the COL2A1 gene and the phenotype yielded a maximal LOD score of 4.51 at theta = 0.00. This result suggests that the structural locus for type II collagen is primarily involved in the pathogenesis of this form of SED. © 1992 Wiley-Liss, Inc.     

Clinical and molecular studies of a large family with desmin-associated restrictive cardiomyopathy

Patients with restrictive cardiomyopathy (RC) have impaired diastolic function, but intact systolic function until later stages of the disease, ultimately leading to heart failure. Primary RC is often sporadic, but also may be inherited in an autosomal dominant fashion, particularly the idiopathic forms. Recently there has been great interest in inherited cardiomyopathy associated with myocyte desmin deposition ('desminopathies'). In some such families, desmin or alpha-B crystallin gene mutation is the underlying cause, and the desmin accumulation affects skeletal muscle as well, usually causing skeletal myopathy. We describe a large family with apparent autosomal dominant inheritance of desmin-associated RC spanning four generations, with the age of onset and severity/rate of progression being highly variable. This family is relatively unique in that there is no symptom-based evidence of skeletal muscle involvement, and the known desminopathy and cardiomyopathy genes/loci have been ruled out. These data support literature suggesting that desmin deposition may be associated with different underlying gene defects, and that a novel desminopathy gene is responsible for the condition in this family.     

Apoptotic and proliferative status in HPV (+) and HPV (-) inverted papilloma patients. Correlation with local recurrence and clinicopathological variables

Inverted papilloma (IP) is a rare sinonasal benign lesion characterized by aggressive biological behavior. Our aim was to evaluate the expression of various proliferation and apoptotic markers and the presence of HPV genotypes in paraffin sections gathered from surgically treated IP patients. Immunohistochemistry for PCNA, bax, cytochrome c and caspase-8 and flow cytometry for the detection of apoptosis, necrosis and ki67 expression were performed. The identification of various HPV subtypes was achieved by nested PCR amplification. Nasal polyps (NP) and specimens from normal nasal epithelium (NE) were used as controls. PCNA was more frequently expressed in IP compared to NE (p=0.04) and caspase-8 and bax staining were less frequently observed in IP compared to NP (p=0.004 and p=0.01 respectively) and NE (p=0.003 and p=0.01, respectively). IP and NP presented significantly higher Ki67 flow cytometry values compared to NE (p<0.001 and p=0.02 respectively). Cytochrome c was more frequently expressed in IP specimens with more prominent inflammation (p=0.02). A low HPV DNA detection rate was observed. Neither HPV status nor any of the apoptotic or proliferative markers studied was associated with the patients' clinicopathological characteristics. Increased Ki67 appeared to correlate with disease recurrence (p=0.01). Increased PCNA and Ki67 and decreased bax and caspase-8 expression indicate that cell proliferation is increased while apoptosis is inhibited in IP, explaining its biological behavior.     

HARD (± E) syndrome: Report of a sixth family with support for autosomal-recessive inheritance

We report on two sibs with hydrocephalus, encephalocele, agyria and ocular anomalies, an association known as the HARD ± E syndrome. This is thought to be the sixth reported family and third instance of familial occurrence of this autosomal-recessive syndrome which deserves consideration in the nosology of every case of neural tube defect (hydrocephalus).     

Linkage studies in spinocerebellar ataxia (SCA)

Data are now available on 9 pedigrees in detail and 4 pedigrees as lod scores only. Linkage to HLA is significant (? = 5.53 at recombination rates of 0.223 in males and 0.327 in females). Tight linkage is excluded. Nine pedigrees which appear to be typical olivopontocerebellar atrophy (OPCA I) have recombination rates of 0.150 in males and 0.300 in females. The remaining 4 pedigrees are clinically atypical or include discrepant data and give no evidence for linkage. The symbol SCA1 is proposed for a locus on chromosome 6 (loosely linked to HLA), at which at least one allele produces OPCA I (Menzel type). It is not yet clear whether other clinical types are determined by alleles at different loci, although this is suggested by several pedigrees, including a Danish pedigree of OPCA with dementia. Linkage evidence will be decisive in delineating the ataxias.     

Chromosome 18 translocation (18;21) (p11.1;p11.1) associated with psychosis in one family

In the course of recruiting families with 2 schizophrenic siblings for genome screening and linkage studies, a family was found with mental retardation, schizophrenia, and/or other related psychotic illnesses in individuals who also had an unbalanced or balanced translocation between chromosomes 21–18 [t(18;21) (p11.1;p11.1)]. The pericentric region of chromosome 18 has already been noted as a possible location of a gene for bipolar psychosis. The family described here provides further evidence that this region should be examined for a candidate psychosis gene. © 1996 Wiley-Liss, Inc.     

Adenocarcinoma arising in gastric inverted hyperplastic polyp: a case report and review of the literature

A 54-year-old man, found to have a submucosal tumor in the stomach by double contrast roentgenography, endoscopy, and endoscopic ultrasonography, underwent a laparoscopic partial gastrectomy. The pathological examination revealed that the lesion, measuring 45 mm x 35 mm, was an inverted hyperplastic polyp (IHP) located in the submucosal layer and consisting mostly of columnar cells resembling foveolar epithelium and pyloric gland cells. Notably, adenocarcinoma with adjacent dysplasia was observed in the submucosal glands. Transition from hyperplasia to dysplasia and from dysplasia to adenocarcinoma was noted. The adenocarcinoma component was intensely and diffusely positive for p53 overexpression, while the dysplasia component showed only weak and focal positivity, suggesting a role of p53 mutation in the dysplasia-carcinoma sequence. Gastric IHP is very rare, and only 31 cases (in 29 patients) have been reported. Five of these IHPs coexisted with gastric adenocarcinomas, which had all developed separately from the IHP lesions. Therefore, this is the first case of adenocarcinoma arising within gastric IHP itself.     

Genetic linkage for Darier disease (keratosis follicularis)

Darier disease is an autosomal dominant skin disorder characterized by abnormal keratinocyte adhesion. Recent data have provided evidence for linkage of the Darier disease locus to 12q23–24.1 in British families. We have carried out linkage analysis using the 12q markers D12S58, D12S84, D12S79, D12S86, PLA2, and D12S63 in 6 Canadian families. Pairwise linkage analysis generated positive lod scores at all 6 markers at various recombination fractions, and each family showed positive lod scores with more than one marker. The peak lod score in the multipoint analysis (Z_max) was 5.5 in the interval between markers D12S58 and D12S84. These positive lod scores in North American families of varied European ancestry confirm the location of the Darier disease gene, and suggest genetic homogeneity. The future identification and sequencing of the gene responsible for Darier disease should lead to improved understanding of the disease and of keratinocyte adhesion in general. © 1995 Wiley-Liss, Inc.     

Genetic studies in a family with testicular feminization, haemophilia A and colour blindness

The mode of inheritance of the syndrome of testicular feminization (tf) is not clear. Linkage studies to date have been inconclusive. A unique family with tf and with haemophilia A and deutan colour blindness is reported. Despite information about three X-chromosomal and several autosomal genetic markers, no definite evidence in favour of X-chromosomal or autosomal inheritance can be presented.     

Short inverted repeats function as hotspots of intermolecular recombination giving rise to oligomers of deleted plastid DNAs (ptDNAs)

We have determined the nucleotide sequences around the junction points of oligomeric-deleted ptDNAs possessing a head-to-head or tail-to-tail configuration from long-term cultured cell lines and albino plants. It was shown that DNA rearrangement occurred by direct fusion of deleted ptDNAs in an inverted orientation, which was linked by an asymmetrical sequence of 254–698 bp derived from either of the ptDNAs joined. It is notable that inverted repeats of 7–14 bp flank the asymmetrical sequences at each of the junction points. These features of the DNA sequence around the junction points are commonly observed in oligomeric ptDNA with a large-scale deletion regardless of the cell lines employed. It is suggested that the short inverted repeats are involved in the intermolecular recombination of ptDNA. Received: 1 July / 21 October 1996     

Linkage mapping of a nonspecific form of X‐linked mental retardation (MRX53) in a large Pakistani family

Nonspecific X‐linked mental retardation is a nonprogressive, genetically heterogeneous condition that affects cognitive function in the absence of other distinctive clinical manifestations. We report here linkage data on a large Pakistani family affected by a form of X‐linked nonspecific mental retardation. X chromosome genotyping of family members and linkage analysis allowed the identification of a new disease locus, MRX53. The defined critical region spans approximately 15 cM between DXS1210 and DXS1047 in Xq22.2–26. A LOD score value of 3.34 at no recombination was obtained with markers DXS1072 and DXS8081. © 2001 Wiley‐Liss, Inc.     

Further characterization of a large inverted repeat in the mitochondrial genomes of Agaricus bisporus (=A. brunnescens) and related species

The mitochondrial (mt) genome of Agaricus bisporus Ag50 (a heterokaryon) is a 136-kilobase (kb) circular molecule which contains a pair of large inverted repeats (IRs). Two large BAMHI fragments (B1 and B2) which contain the IR regions were further mapped. The repeated regions were determined to be approximately 7.7 kb in length. The mt small ribosomal RNA (S rRNA) gene is located adjacent to one of the repeated regions. Orientational isomers, generated by homologous recombination between the repeated regions, were not observed in mtDNA extractions from Ag50 mycelium (liquid culture) or from Ag50 fruit bodies. We also did not observe any orientational isomers in Ag50HA or Ag50HB, two homokaryons somatically isolated from Ag50. DNA homologous to the Ag50 mt repeated regions was observed in ten other isolates of Agaricus including four isolates of A. bisporus, two isolates of A. subperonatus, two isolates of A. subfloccosus, one isolate of A. bitorquis, and one isolate of A. pattersonae. The repeated regions and the small unique regions in two other heterokaryotic strains of A. bisporus, Ag2 and Ag85, were physically mapped. The repeated regions in these two strains are also in the inverted forms. Restriction endonuclease mapping indicated that the two copies of the IR in Ag85 were not identical.     

Linkage in a family with X-linked Charcot-Marie-Tooth disease

The gene for the X-linked form of Charcot-Marie-Tooth disease (CMT Peroneal Muscular Atrophy, X-linked: McKusick No. 30280) has been shown in a single family to be linked to DXYS1 with a lod score of 4.55 at a recombination fraction of 0.03 and to PGK1 with a lod score of 3.34 at zero recombination. This is in agreement with previous work based on several families. Pooled data from this family and 7 previously reported families give a maximum lod score of 12.04 at theta max of 0.05 for linkage between CMTX and DXYS1 loci.     

一个遗传性多发性骨软骨瘤家系的基因突变检测

目的 确定一个遗传性多发性骨软骨瘤(hereditary multiple exostoses,HME)家系的致病基因.方法 应用与EXT1、EXT2紧密连锁的短串联重复序列(short tandem repeat,STR)对该家系进行连锁分析,确定候选基因,然后对候选基因的编码区及外显子与内含子交界处进行PCR-测序法突变分析.结果 该家系致病基因被定位在EXT2基因区,测序发现EXT2基因536G>A无义突变,该突变位于EXT2基因第3外显子,导致编码第180位氨基酸的密码子成为终止密码,突变与疾病共分离,其余外显子未发现突变.另发现1例外显不全.结论 EXT2基因536G>A突变是导致这个家系发生骨软骨瘤的原因.     

X-linked severe mental retardation and a progressive neurological disorder in a Belgian family: clinical and genetic studies

The combination of X-linked mental retardation (XLMR) and neurological disorders occurs in a number of syndromes. Differential diagnosis mostly depends on clinical data and mapping of responsible genes by linkage analysis. We present a Belgian family with severe XLMR and a progressive neurological disorder with ataxia, spasticity and convulsions. Biochemical investigations, neuroimaging and neuropathology were normal. Linkage analysis pointed to region Xq27–28 as the probable locus for the genetic defect. The sequence of the LI CAM cDNA, a possible candidate gene, proved to be normal in the patients. This suggests the presence of a genetic factor on Xq27–28, different from LI CAM, which can lead to severe XLMR and a progressive neurological disorder.