Association of cleft lip and atrial septal defect in mice: a preliminary report.

Newborn A/J and CL/Fr mice with congenital cleft lip usually have an atrial septal defect of the secundum type, often associated with cyanosis. Their littermates without cleft lip rarely have a septal defect. The atrial septal defect results from a delay in growth of the atrial septum primum.     

The gene coding a ubiquitin-activating enzyme may locate on X chromosome

tsBN75 cells which have a ts defect in the S phase have a mutation linked to the gene of hypoxanthine phosphoribosyl transferase and cannot complement ts85 cells which have a ts defect in the ubiquitin-activating enzyme. The ubiquitin-activating enzyme may be required for completion of the S phase.     

Genetic sperm defects

Genetic sperm defects are specific sperm defects, which have been shown to have a genetic mode of transmission. Such genetic linkage, either direct or indirect, has been associated with a number of sperm defects in different species, with this number increasing with improved diagnostic capabilities. A number of sperm defects, which have proven or suspected genetic modes of transmission are discussed herein, with particular emphasis on cattle. These include: 1. Acrosome defects (knobbed, ruffled and incomplete); 2. Head defects (abnormal condensation, decapitated, round head, rolled head, nuclear crest); 3. Midpiece abnormalities ("Dag" defect, "corkscrew" defect, "pseudo-droplet" defect); 4. Tail defects ("tail stump" defect, primary ciliary dyskinesia).     

A large, dominant pedigree of atrioventricular septal defect (AVSD): exclusion from the Down syndrome critical region on chromosome 21.

We describe a large pedigree of individuals with autosomal dominant atrioventricular septal defect (AVSD). The pedigree includes affected individuals and individuals who have transmitted the defect but are not clinically affected. AVSDs are a rare congenital heart malformation that occurs as only 2.8% of isolated cardiac lesions. They are the predominant heart defect in children with Down syndrome, making chromosome 21 a candidate for genes involved in atrioventricular septal development. We have carried out a linkage study in the pedigree by using 10 simple-sequence polymorphisms from chromosome 21. Multipoint linkage analysis gives lod scores of less than -2 for the region of trisomy 21 associated with heart defects, which excludes a locus within this region as the cause of the defect in this family.     

Identification, genomic organization, chromosomal mapping and mutation analysis of the human INV gene, the ortholog of a murine gene implicated in left-right axis development and biliary atresia

Determination of left-right axis is a precocious embryonic event, and all phenotypic anomalies resulting from disruption of the normal lateralization process are collectively referred to as the lateralization defect. A transgenic mouse with lateralization defect and hepatic, kidney, and pancreatic anomalies has resulted from disruption of the inv gene by insertion of a transgene. The human ortholog is thus a good candidate for lateralization defect in humans, in particular in cases with associated hepatic anomalies. Here, we have identified, mapped, and characterized the INV human gene and screened a series of heterotaxic patients (with or without biliary anomalies) for mutation in this gene. In a German family of Turkish origin, we have found that all available affected and unaffected individuals are heterozygous for a mutation in the splicing donor site of intron 12 in the INV gene resulting in two different aberrant splicing isoforms. This can be explained either by a randomization of lateralization defects or, as suggested earlier, di- or trigenic inheritance, although we have been unable to detect, in this family, a mutation in genes known to be involved in the human lateralization defect ( LEFTY1, LEFTY2, ACVR2B, NODAL, ZIC3, and CFC1). In contrast to the mouse, the affected individuals have no biliary anomalies, and the absence of mutation in a series of seven cases with lateralization defect and biliary anomalies demonstrates that INV is not frequently involved in such a phenotype in humans.     

Kinetic analysis of lamB mutants suggests the signal sequence plays multiple roles in protein export

We have developed a quantitative assay to measure the rate of processing of precursor LamB into mature protein and have used this assay to characterize 10 previously isolated and 3 new lamB signal sequence mutants. The data suggest that the LamB signal sequence serves a complex function. Our assay has revealed five types of signal sequence defect: 1) a strong kinetic defect resulting from alteration of the secondary structure in the putative alpha-helical region in the hydrophobic core, 2) a strong, or 3) a weak kinetic defect due to placement of a charged residue in the hydrophobic core, 4) decreased synthesis of LamB, and 5) both a decrease in synthesis and a strong kinetic defect. The effect of an extragenic suppressor, prlA4 on the rate of processing pLamB containing signal sequence mutations was also examined and compared to the rates in wild-type strains. It was found that prlA4 increases the rate of processing in some, but not all, mutants having a kinetic defect while having no effect on the decreased synthesis seen in mutants of types 4 and 5.     

The molecular basis of C6 deficiency in the western Cape, South Africa

Deficiency of the sixth component of human complement (C6) has been reported in a number of families from the western Cape, South Africa. Meningococcal disease is endemic in the Cape and almost all pedigrees of total C6 deficiency (C6Q0) have been ascertained because of recurrent disease. We have sequenced the expressed exons of the C6 gene from selected cases and have found three molecular defects leading to total deficiency: 879delG, which is the common defect in the Cape and hitherto unreported, and 1195delC and 1936delG, which have been previously reported in African-Americans. We also show that the 879delG and 1195delC defects are associated with characteristic C6/C7 region DNA marker haplotypes, although small variations were observed. The 1936delG defect was observed only once in the Cape, but its associated haplotype could be deduced. The data from the haplotypes indicate that these three molecular defects account for the defects in all the 38 unrelated C6Q0 individuals we have studied from the Cape. We have also observed the 879delG defect in two Dutch C6-deficient kindreds, but the 879delG defect in the Cape probably did not come from the Netherlands. Received: 17 April 1998 / Accepted: 19 June 1998     

The Dag defect of the tail of the bull sperm. Studies on the inheritance and pathogenesis

During the period 1963–1979, 15 spontaneous cases of the sterilizing Dag defect of the sperm tail in Danish Jersey bulls have been examined. The pedigree of these bulls could be traced back through both paternal and maternal lines to a common ancestor bull born in 1934. The probable heredity of the defect was tested in a sire-daughter breeding experiment. Six bulls out of 38 sons born produced semen typical of the Dag defect thus confirming that the defect is due to the presence of an autosomal recessive factor. Systematic examination of the epididymal contents from 17 bulls revealed that the defect consistently developed in the distal part of the epididymal caput. Neither biophysical and biochemical qualities of the epididymal contents nor the histological appearance of the duct epithelium differed from the findings in normal bulls.     

Palatal slit: a new spontaneous defect of the palate of C57BL/6 mice

A hitherto undescribed palatal defect, here named "palatal slit," was observed during a teratological study of C57BL/6 fetuses. The defect, involving a failure of fusion of the premaxilla and palatal shelves, corresponds to stage 7 in normal palate closure. Adult C57BL/6 mice have been observed with the defect, so it does not represent a developmental delay that is repaired postnatally. Genetic factors of an unknown nature seem to be involved in the occurrence of palatal slit, which does not appear to be related developmentally to cleft palate. Some preliminary information on the defect is reported here.     

Cytokine dysregulation induced by apoptotic cells is a shared characteristic of macrophages from nonobese diabetic and systemic lupus erythematosus-prone mice

Macrophages from nonobese diabetic (NOD) mice, which spontaneously develop type I diabetes, share a defect in elicited cytokine production with macrophages from multiple diverse strains of systemic lupus erythematosus (SLE)-prone mice. We have previously shown that, in SLE-prone mice, this defect is triggered by exposure to apoptotic cells. We report in this work that macrophages from prediseased NOD mice also respond abnormally to apoptotic cells, mimicking closely the apoptotic cell-dependent abnormality that we have observed in multiple SLE-prone strains. This defect is characterized by the underexpression of IL-1 beta and multiple other cytokines. In the presence of apoptotic cells or FBS, elicited expression of IL-1 beta by NOD macrophages is markedly reduced compared with that by macrophages from control mice, including three strains of mice that develop type II (nonautoimmune) diabetes. Given the increasing role of apoptotic cells in tolerance and autoimmunity, a macrophage defect triggered by apoptotic cells has broad potential to upset the balance between tolerance and immunity. The concordance of this defect among so many diverse autoimmune-prone strains suggests that the genetic basis for this abnormality may constitute a permissive background for autoimmunity.     

Cystinosis: A defect of lysosomal cystine efflux

The metabolic defect which results in the accumulation of cystine within tissues of children with the recessively inherited disease cystinosis has baffled investigators for almost half a century. Investigations by numerous laboratories have finally culminated in the delineation of the basic defect in this unusual disorder.     

Cytokine dysregulation induced by apoptotic cells is a shared characteristic of murine lupus

Of the multiple murine models of autoimmunity, the three most closely resembling human systemic lupus erythematosus (SLE) are the MRL/lpr, New Zealand Black/White F(1), and male BXSB. Although these strains share many disease characteristics, no common cellular defect has previously been found in prediseased mice from all these strains. We show in this study that macrophages from prediseased mice of all three SLE-prone strains, as well as macrophages from mice whose genomes contribute to the development of SLE (MRL/+, New Zealand White, New Zealand Black, female BXSB, and LG/J), have an identical and profound defect in cytokine expression that is triggered by apoptotic cells. Strikingly, none of 13 nonautoimmune strains tested exhibited this defect. Given that apoptotic Ags have been increasingly recognized as the target of autoantibodies, a defect in cytokine expression that is triggered by apoptotic cells has broad potential to upset the balance between tolerance and immunity.     

Evidence that mating by the Saccharomyces cerevisiae gpa1Val50 mutant occurs through the default mating pathway and a suggestion of a role for ubiquitin-mediated proteolysis.

The yeast G alpha subunit, Gpa1p, plays a negative role in the pheromone response pathway. The gpa1Val50 mutant was previously shown to have a growth defect, consistent with the GTPase defect predicted for this mutation, and greatly reduced mating. Various explanations for the mating defect have been proposed. One approach to analyze the gpa1Val50 mating defect involved epistasis analysis. The low mating of the gpa1Val50 mutant was independent of the pheromone receptor; therefore, it results from intracellular activation of the pathway, consistent with a GTPase defect. This result suggests that gpa1Val50 mating occurs through the default rather than the chemotropic pathway involved in pheromone response. We therefore tested the effect of a spa2 mutation on gpa1Val50 mating, because Spa2p has been implicated in the default pathway. The spa2 mutation greatly reduced the mating of the gpa1Val50 mutant, suggesting that gpa1Val50 mating occurs predominantly through the default pathway. In a second approach to investigate the gpa1Val50 phenotypes, suppressors of the gpa1Val50 mating defect were isolated. Two suppressor genes corresponded to SON1/UFD5 and SEN3, which are implicated in ubiquitin-mediated proteolysis. On the basis of these results, we suggest that a positive component of the default mating pathway is subject to ubiquitin-mediated degradation.     

C1 binding by mouse IgM. The effect of abnormal glycosylation at position 402 resulting from a serine to asparagine exchange at residue 406 of the mu-chain

We have previously shown that IgM-Asn406, a mutant IgM which has asparagine in place of the serine which is normally found at position 406, also has an abnormally glycosylated mu-chain and is defective in complement-dependent cytolysis. Here we show by analyzing cyanogen bromide fragments from normal and mutant mu-chains that the site of abnormal glycosylation is at the neighboring position, Asn402. The cytolytic defect was shown to be due to impaired C1 binding. At physiological ionic strength, the C1 binding defect was estimated to be 12-fold, which correlates well with the measured defect in cytolytic activity; also, the severity of the defect in C1 binding by the mutant protein decreases with decreasing ionic strength. Kinetic studies showed that the difference in affinities is due to a proportional difference in the association rate for C1q. By comparing IgM made in the presence and absence of deoxymannojirimycin, we show further that the defect in cytolytic activity derives mostly from the abnormal oligosaccharide.     

The effect of defect size on the stress concentration and fracture characteristics for a tubular torsional model with a transverse hole

The maximum stress location and crack resistance of a tubular torsional model with varying transverse circular defects were determined by the use of experimental and global-local finite element modeling techniques. The experimental results showed that the reduction in torsional strength was inversely proportional to defect size. In addition, the maximum stress location around the defect was closely related to the normalized defect diameter. By measuring the shifted angle associated with each defect ratio, a linear relationship, delta theta = -6.28 + 0.55*(d/D), was determined. Finite element results indicated that the stress concentration factor, Kg, for a single-cortex defect is similar to that of a double-cortex defect of identical dimension. Application of the strain energy density (SED) theory proposed by Sih and Oliveira Faria (Fracture Mechanics Methodology, Martinus Nijhoff, The Hague, 1984), indicated that the fracture toughness, KIC, for large defects was greater than that for small defects. This implies that tubular structures with large defects have a greater resistance to crack initiation and growth.     

人类心脏发育缺陷的分子机理

为了探索心脏发育的缺陷及遗传机制以及在分子水平上先天性心脏病的发生机理,概述了人类心脏发育缺陷的研究进展,包括人类心脏不对称发育、心脏发育缺陷和心脏缺陷的分子机理.     

Heritable ventricular septal defect in Yucatan miniature swine

A heritable ventricular septal defect (VSD) was found in a strain of Yucatan miniature swine. The defect was determined to be a high membranous VSD analogous in anatomic location to the most common from of VSD in humans. Eighteen animals were studied clinically, hemodynamically and at necropsy to characterize the defect. Three mature animals developed pulmonary hypertension. Three animals were found to have a patent foramen ovale (PFO) in addition to the VSD. VSD is heritable probably due to polygenic factors. VSD in Yucatan miniature swine may be a suitable model of the human disease syndrome.     

Epimutations in Prader-Willi and Angelman syndromes: a molecular study of 136 patients with an imprinting defect

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are neurogenetic disorders that are caused by the loss of function of imprinted genes in 15q11-q13. In a small group of patients, the disease is due to aberrant imprinting and gene silencing. Here, we describe the molecular analysis of 51 patients with PWS and 85 patients with AS who have such a defect. Seven patients with PWS (14%) and eight patients with AS (9%) were found to have an imprinting center (IC) deletion. Sequence analysis of 32 patients with PWS and no IC deletion and 66 patients with AS and no IC deletion did not reveal any point mutation in the critical IC elements. The presence of a faint methylated band in 27% of patients with AS and no IC deletion suggests that these patients are mosaic for an imprinting defect that occurred after fertilization. In patients with AS, the imprinting defect occurred on the chromosome that was inherited from either the maternal grandfather or grandmother; however, in all informative patients with PWS and no IC deletion, the imprinting defect occurred on the chromosome inherited from the paternal grandmother. These data suggest that this imprinting defect results from a failure to erase the maternal imprint during spermatogenesis.