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PubMed1970

Effects of chronic excess salt ingestion. Inheritance of hypertension in the rat.

TWO STRAINS OF RAT HAVE BEEN DEVELOPED BY SELECTIVE BREEDING: one strain (R rats) is resistant to salt hypertension, the other strain (S rats) is highly susceptible. The inheritance of these traits has been explored in the first (F(1)) and second (F(2)) generation of crossbred rats and in backcrosses between parent and first filial (F(1) x R, F(1) x S) generations. Male F(1) rats had an average blood pressure close to the mid-parental (R and S) values, and the average of F(2) males was equivalent to that of F(1). Male offspring of F(1) with R, or F(1) with S also showed averages close to the respective mid-parental values. Female offspring showed deviations from this linear relationship, indicating a significant dominance in the female for the genes of normal blood pressure. A model of two autosomal, nonlinked diallelic loci, with a dominance deviation at one locus in the female, gave predictions with a reasonable agreement to the observed values. The same model also appeared compatible with human data if we assume a gene frequency of 0.13 for the hypertensinogenic allele on both loci. Random fluctuations in blood pressure, and incomplete homogeneity of parental strains permit several alternative models. The major conclusions are: that more than one locus is needed to explain the findings though as few as two loci may possibly suffice; the allelic effect seems additive in males, but there is a sex-determined influence on the expression in females; there is no consistent evidence for sex-linked inheritance. Furthermore, this model developed from the study of rats may provide a framework for analysis of human data.

Analysis of Variance↗
PubMed1971

The inheritance of individual antigenic specificities of rabbit antibodies to streptococcal carbohydrates.

The inheritance of individual antigenic specificities (IAS) of rabbit antibodies to the Group C streptococcal carbohydrate was demonstrated in a selectively bred rabbit family. The IAS of the antibodies from 3 proband rabbits were also observed in the Group C antibodies in as many as 7 out of 42 related rabbits, but in none of the Group C antibodies from 48 unrelated rabbits, Immunodiffusion analyses and quantitative radioprecipitin experiments revealed that this cross-specificity may be either partial or complete. Quantitative inhibition of the precipitin reaction between the proband antibody and its antiserum by preimmune IgG revealed 30-fold differences in the proportion of molecules with cross-specificity for the proband antibody. This proportion is higher in the preimmune IgG of the proband rabbit and of those relatives which produced cross-precipitating antibodies than it is in the IgG of rabbits which had the same group a allotype, but did not produce cross-precipitating antibodies. The proportion is much lower in the IgG of rabbits with a group a allotype different from that of the proband antibody. These data suggest that serologically detected individual antigenic specificities are inherited markers of immunoglobulins.

Amino Acid Sequence↗
PubMed1992

The immune response to hepatitis B vaccine in humans: inheritance patterns in families.

We have recently shown that the human antibody response to the hepatitis B virus surface antigen (HBsAg) vaccine is major histocompatibility complex (MHC) associated. In studies of nonresponders to the vaccine, we found an increased incidence of individuals homozygous for human histocompatibility leukocyte antigen (HLA) proteins associated with the extended (conserved) haplotype [HLA-B8,SC01,DR3]. In later prospective vaccination trials, we showed that none of five individuals homozygous for this haplotype developed more than 1,300 radioimmunoassay (RIA) units of antibody (mean, 467 RIA units), while all heterozygotes made at least 2,500 RIA units (mean antibody level, 15,608 units). Our results suggested that [HLA-B8,SC01,DR3] lacks an immune response gene for HBsAg, and that response is inherited in a dominant fashion. To provide further evidence for this hypothesis, we have now analyzed the results of HBsAg immunization in families. 43 members of 10 families were immunized with the hepatitis B vaccine, including seven families where at least one member bore the haplotype [HLA-B8,SC01,DR3], and three families where one member had already received, but failed to respond to, the vaccine. In two of these three families, the presence of [HLA-B8,SC01,DR3] was subsequently found. Of nine MHC-identical sibling pairs in the study, both members of eight pairs had similar antibody responses (five nonresponder and three responder pairs). In all families with such sibling pairs, including the discordant pair, rank-ordering members by antibody level demonstrated that no relative's value came between the sibling pair values. Furthermore, of nine [HLA-B8,SC01,DR3]-haplotype-homozygous individuals, six were nonresponders, and two others had only low-normal responses. [HLA-B8,SC01,DR3]-heterozygous family members always had higher levels of antibody than their homozygous relatives. Linkage analysis of nonresponse to HLA haplotypes revealed a maximum likelihood LOD (logarithm of the odds) score of 6.3 at a recombination fraction of 0.1. The MHC association with lack of antibody response to HBsAg was not seen with tetanus immunization, where 1 of 20 HBsAg responders and 1 of 21 poor or nonresponders had tetanus titers of less than 1:512; both tetanus nonresponders were [HLA-B8,SC01,DR3] heterozygotes. Our results indicate that: (a) response to the HBsAg vaccine is MHC linked, and inherited in a dominant fashion; (b) an abnormal or missing immune response (Ir) gene for HBsAg is a characteristic of most examples of the extended haplotype [HLA-B8,SC01,DR3]; and (c) other haplotypes also have abnormal or missing Ir genes for HBsAg.

Female↗
PubMed1998

Inheritance of astigmatism: evidence for a major autosomal dominant locus.

Although astigmatism is a frequent refractive error, its mode of inheritance remains uncertain. Complex segregation analysis was performed, by the POINTER and COMDS programs, with data from a geographically well-defined sample of 125 nuclear families of individuals affected by astigmatism. POINTER could not distinguish between alternative genetic models, and only the hypothesis of no familial transmission could be rejected. After inclusion of the severity parameter, COMDS results defined a genetic model for corneal astigmatism and provided evidence for single-major-locus inheritance. These results suggest that genetic linkage studies could be implemented and that they should be limited to multiplex families with severely affected individuals.

Adult↗
PubMed1999

Identification of a genetic defect in the hairless gene in atrichia with papular lesions: evidence for phenotypic heterogeneity among inherited atrichias.

Recently, we showed that atrichia with papular lesions (APL), a rare inherited form of alopecia, is transmitted as an autosomal recessive trait in a large inbred kindred of Israeli-Arab origin. Furthermore, we mapped the APL locus to a 5-cM region of chromosome 8p12 in this family. The human "hairless" gene is a candidate target gene for the disease mutation because it maps to the APL locus and because it was recently found to be mutated in a related but clinically distinct form of alopecia known as "alopecia universalis" or "congenital alopecia." In the present study, the coding sequence of the hairless gene was compared by reverse transcription-PCR in fibroblast cell lines derived from an affected patient and an unrelated individual. We identified a single-base deletion (3434delC) in the hairless gene that cosegregated with the disease phenotype in the family. This deletion is predicted to cause a frameshift mutation in the highly conserved C-terminal part of the hairless protein, a region putatively involved in the transcription factor activity of the hairless gene product. The present results are indicative of phenotypic heterogeneity in inherited atrichias caused by mutations in the hairless gene, suggesting different roles for the regions mutated in APL and in other forms of congenital atrichia during hair development.

Age of Onset↗
PubMed2000

Familial mental retardation syndrome ATR-16 due to an inherited cryptic subtelomeric translocation, t(3;16)(q29;p13.3).

In the search for genetic causes of mental retardation, we have studied a five-generation family that includes 10 individuals in generations IV and V who are affected with mild-to-moderate mental retardation and mild, nonspecific dysmorphic features. The disease is inherited in a seemingly autosomal dominant fashion with reduced penetrance. The pedigree is unusual because of (1) its size and (2) the fact that individuals with the disease appear only in the last two generations, which is suggestive of anticipation. Standard clinical and laboratory screening protocols and extended cytogenetic analysis, including the use of high-resolution karyotyping and multiplex FISH (M-FISH), could not reveal the cause of the mental retardation. Therefore, a whole-genome scan was performed, by linkage analysis, with microsatellite markers. The phenotype was linked to chromosome 16p13.3, and, unexpectedly, a deletion of a part of 16pter was demonstrated in patients, similar to the deletion observed in patients with ATR-16 syndrome. Subsequent FISH analysis demonstrated that patients inherited a duplication of terminal 3q in addition to the deletion of 16p. FISH analysis of obligate carriers revealed that a balanced translocation between the terminal parts of 16p and 3q segregated in this family. This case reinforces the role of cryptic (cytogenetically invisible) subtelomeric translocations in mental retardation, which is estimated by others to be implicated in 5%-10% of cases.

Abnormalities, Multiple↗
PubMed2000

Segregation analysis in Shwachman-Diamond syndrome: evidence for recessive inheritance.

Shwachman-Diamond syndrome is a rare disorder of unknown cause. Reports have indicated the occurrence of affected siblings, but formal segregation analysis has not been performed. In families collected for genetic studies, the mean paternal age and mean difference in parental ages were found to be consistent with the general population. We determined estimates of segregation proportion in a cohort of 84 patients with complete sibship data under the assumption of complete ascertainment, using the Li and Mantel estimator, and of single ascertainment with the Davie modification. A third estimate was also computed with the expectation-maximization (EM) algorithm. All three estimates supported an autosomal recessive mode of inheritance, but complete ascertainment was found to be unlikely. Although there are no overt signs of disease in adult carriers (parents), the use of serum trypsinogen levels to indicate exocrine pancreatic dysfunction was evaluated as a potential measure for heterozygote expression. No consistent differences were found in levels between parents and a normal control population. Although genetic heterogeneity cannot be excluded, our results indicate that simulation and genetic analyses of Shwachman-Diamond syndrome should consider a recessive model of inheritance.

Abnormalities, Multiple↗
PubMed2000

The inheritance of neuropsychological dysfunction in twins discordant for schizophrenia.

While genetic influences in schizophrenia are substantial, the disorder's molecular genetic basis remains elusive. Progress has been hindered by lack of means to detect nonpenetrant carriers of the predisposing genes and by uncertainties concerning the extent of locus heterogeneity. One approach to solving this complexity is to examine the inheritance of pathophysiological processes mediating between genotype and disease phenotype. Here we evaluate whether deficits in neurocognitive functioning covary with degree of genetic relationship with a proband in the unaffected MZ and DZ co-twins of patients with schizophrenia. Twin pairs discordant for schizophrenia were recruited from a total population cohort and were compared with a demographically balanced sample of control twin pairs, on a comprehensive neuropsychological test battery. The following four neuropsychological functions contributed uniquely to the discrimination of degree of genetic loading for schizophrenia and, when combined, were more highly correlated within MZ pairs than within DZ pairs, in both discordant and control twins: spatial working memory (i.e., remembering a sequence of spatial locations over a brief delay), divided attention (i.e., simultaneous performance of a counting and visual-search task), intrusions during recall of a word list (i.e., "remembering" nonlist items), and choice reaction time to visual targets. Together with evidence from human and animal studies of mediation of these functions by partially distinct brain systems, our findings suggest that there are multiple independently inherited dimensions of neural deficit in schizophrenia and encourage a search for genes contributing to quantitative variation in discrete aspects of disease liability. On tests of verbal and visual episodic memory, but not on the liability-related measures, patients were more impaired than their own MZ co-twins, suggesting a preferential impact of nongenetic influences on long-term memory systems.

Adult↗
PubMed1999

Protection against human immunodeficiency virus type 1 infection in persons with repeated exposure: evidence for T cell immunity in the absence of inherited CCR5 coreceptor defects.

It has been hypothesized that protection against human immunodeficiency virus (HIV)-1 infection may result from either acquired host immunity, inheritance of a dysfunctional CCR5 HIV-1 coreceptor, or a low or attenuated virus inoculum. Thirty-seven HIV-1-uninfected persons engaging in repeated high-risk sexual activity with an HIV-1-infected partner were prospectively studied to determine the contribution of these factors in protecting against HIV-1 transmission. More than one-third (13/36) demonstrated HIV-1-specific cytotoxicity, and this activity significantly correlated with the wild type CCR5 genotype (P=.03). Only 1 subject (3%) demonstrated the homozygous CCR5 32-bp deletion (Delta32/Delta32). Median plasma HIV-1 RNA levels from 18 HIV-1-infected sex partners were not statistically different from those of matched infected control patients. These results indicate that inheritance of the Delta32 CCR5 mutation does not account for the majority of persistently HIV-1-resistant cases, and the presence of cellular immunity in these persons suggests either undetected infection or protective immunity.

Acquired Immunodeficiency Syndrome↗
PubMed2001

Efficient multipoint linkage analysis through reduction of inheritance space.

Computational constraints currently limit exact multipoint linkage analysis to pedigrees of moderate size. We introduce new algorithms that allow analysis of larger pedigrees by reducing the time and memory requirements of the computation. We use the observed pedigree genotypes to reduce the number of inheritance patterns that need to be considered. The algorithms are implemented in a new version (version 2.1) of the software package GENEHUNTER. Performance gains depend on marker heterozygosity and on the number of pedigree members available for genotyping, but typically are 10-1,000-fold, compared with the performance of the previous release (version 2.0). As a result, families with up to 30 bits of inheritance information have been analyzed, and further increases in family size are feasible. In addition to computation of linkage statistics and haplotype determination, GENEHUNTER can also perform single-locus and multilocus transmission/disequilibrium tests. We describe and implement a set of permutation tests that allow determination of empirical significance levels in the presence of linkage disequilibrium among marker loci.

Algorithms↗
PubMed2002

BBS4 is a minor contributor to Bardet-Biedl syndrome and may also participate in triallelic inheritance.

Bardet-Biedl syndrome (BBS) is an uncommon multisystemic disorder characterized primarily by retinal dystrophy, obesity, polydactyly, and renal dysfunction. BBS has been modeled historically as an autosomal recessive trait, under which premise six independent BBS loci (BBS1-BBS6) have been mapped in the human genome. However, extended mutational analyses of BBS2 and BBS6, the first two BBS genes cloned, suggest that BBS exhibits a more complex pattern of inheritance, in which three mutations at two loci simultaneously are necessary and sufficient in some families to manifest the phenotype. We evaluated the spectrum of mutations in the recently identified BBS4 gene with a combination of haplotype analysis and mutation screening on a multiethnic cohort of 177 families. Consistent with predictions from previous genetic analyses, our data suggest that mutations in BBS4 contribute to BBS in <3% of affected families. Furthermore, integrated mutational data from all three currently cloned BBS genes raise the possibility that BBS4 may participate in triallelic inheritance with BBS2 and BBS1, but not the other known loci. Establishment of the loci pairing in triallelism is likely to be important for the elucidation of the functional relationships among the different BBS proteins.

Alleles↗
PubMed2004

Hypergonadotropic ovarian failure associated with an inherited mutation of human bone morphogenetic protein-15 (BMP15) gene.

Hypergonadotropic ovarian failure is a common cause of female infertility. It is a heterogeneous disorder that, in the most severe forms, is a result of ovarian dysgenesis (OD). Most OD cases are associated with major X-chromosome abnormalities, but the pathogenesis of this disorder is still largely undefined in patients with a normal karyotype. Animal models showed the important role in female reproduction played by the product of a gene located at Xp11.2 in humans (BMP15). BMP15 is an oocyte-specific growth/differentiation factor that stimulates folliculogenesis and granulosa cell (GC) growth. We report two sisters with a normal karyotype who are affected with hypergonadotropic ovarian failure due to OD. The familial presentation suggested a genetic origin, and candidate genes were screened for mutations. A heterozygous nonconservative substitution in the pro region of BMP15 (Y235C) was identified in both sisters but not in 210 control alleles. This mutation was inherited from the father. Mutant BMP15 appears to be processed abnormally, is associated with reduced GC growth, and antagonizes the stimulatory activity of wild-type protein on GC proliferation. In conclusion, the first natural mutation in human BMP15 is associated with familial OD, indicating that the action of BMP15 is required for the progression of human folliculogenesis. This condition represents an exceptional example of X-linked human disease exclusively affecting heterozygous females who inherited the genetic alteration from the unaffected father. BMP15 defects are involved in the pathogenesis of hypergonadotropic ovarian failure in humans.

Adolescent↗
PubMed2005

A 4-bp deletion in the Birt-Hogg-Dubé gene (FLCN) causes dominantly inherited spontaneous pneumothorax.

Primary spontaneous pneumothorax (PSP), a condition in which air enters the pleural space and causes secondary lung collapse, is mostly sporadic but also occurs in families. The precise etiology of PSP remains unknown, although it is associated with emphysemalike changes (bullae) in the lungs of almost all patients. We describe the results of a genetic study of a large Finnish family with a dominantly inherited tendency to PSP. A genomewide scan suggested linkage to chromosome 17p11. Screening of the best candidate gene, FLCN, revealed a 4-bp deletion in the first coding exon, which causes a frameshift that predicts a protein truncation 50 missense amino acids downstream. All carriers of the deletion had bullous lung lesions. Mutations in FLCN are also responsible for Birt-Hogg-Dubé (BHD) syndrome (a dominantly inherited disease characterized by benign skin tumors, PSP, and diverse types of renal cancer) and, rarely, are detected in sporadic renal and colorectal tumors. Unlike other FLCN mutations, the exon 4 deletion seems to be associated with bullous lung changes only with 100% penetrance. These results suggest that changes in FLCN may have an important role in the development of PSP and, more importantly, of emphysema, a chronic pulmonary disease that often leads to formation of bullous lesions and lowered pulmonary function. Additionally, given the strong association of PSP and BHD, the connection between these conditions needs to be investigated further, particularly in patients with familial PSP, who may be at a greater risk of developing renal cancer.

Base Sequence↗
PubMed2006

Absence of a paternally inherited FOXP2 gene in developmental verbal dyspraxia.

Mutations in FOXP2 cause developmental verbal dyspraxia (DVD), but only a few cases have been described. We characterize 13 patients with DVD--5 with hemizygous paternal deletions spanning the FOXP2 gene, 1 with a translocation interrupting FOXP2, and the remaining 7 with maternal uniparental disomy of chromosome 7 (UPD7), who were also given a diagnosis of Silver-Russell Syndrome (SRS). Of these individuals with DVD, all 12 for whom parental DNA was available showed absence of a paternal copy of FOXP2. Five other individuals with deletions of paternally inherited FOXP2 but with incomplete clinical information or phenotypes too complex to properly assess are also described. Four of the patients with DVD also meet criteria for autism spectrum disorder. Individuals with paternal UPD7 or with partial maternal UPD7 or deletion starting downstream of FOXP2 do not have DVD. Using quantitative real-time polymerase chain reaction, we show the maternally inherited FOXP2 to be comparatively underexpressed. Our results indicate that absence of paternal FOXP2 is the cause of DVD in patients with SRS with maternal UPD7. The data also point to a role for differential parent-of-origin expression of FOXP2 in human speech development.

Apraxias↗
PubMed1986

Transgenic progeny inherit tissue-specific expression of rat elastase I genes.

Six different lines of transgenic mice bearing rat elastase I genes stably inherit both the high-level pancreatic expression and low-level nonpancreatic expression characteristic of each original founding mouse. The high pancreatic expression of the introduced rat genes is transcriptionally determined. In response to high rat elastase I mRNA content in the pancreas, rat elastase I protein is synthesized and secreted at high levels. The stable inheritance of expression of the foreign rat elastase I genes in transgenic mice allows the development of animal lines that synthesize and secrete high levels of foreign protein by the pancreas.

Animals↗
PubMed2006

Analysis of inherited genetic variants in ret proto-oncogene of Brazilian patients with apparently sporadic medullary thyroid carcinoma.

Mutations in different exons of ret proto-oncogene are responsible for the development of medullary thyroid carcinoma (MTC). The mutations can occur as sporadic or as part of multiple endocrine neoplasia (MEN) type 2 hereditary syndromes. Here we report the first focused study of sporadic MTC in Brazilian patients regarding clinical and molecular analysis of ret proto-oncogene. Our study seeks to estimate the risk of hereditary MTC cases among apparently sporadic cases in a Brazilian population and describe ret genetic variants in their germinative lineage. Germinative sequence variants were screened by DNA sequencing and denaturing gradient gel electrophoresis (DGGE) analysis of exons 10, 11, 13, 14, 15, and 16 of 24 Brazilian patients with apparently sporadic MTC. We identified 1 inherited case of 24 (4%) patients with apparently sporadic MTC. Polymorphisms for the ret proto-oncogene coding region were identified in codon 769 of exon 13 (LeuCTT--> LeuCTG) at a frequency of 13% (3/24) and in codon 904 of exon 15 (SerTCC--> SerTCG) at a frequency of 16.6% (4/24). The observed frequency (4%) of inherited disease among apparent sporadic MTC strengthens routine application of ret proto-oncogene germinative DNA screening in all cases of apparently sporadic MTC ascertained at Brazilian cancer hospitals.

Adult↗
PubMed1995

A mating type-linked mutation that disrupts the uniparental inheritance of chloroplast DNA also disrupts cell-size control in Chlamydomonas.

An intriguing feature of early zygote development in Chlamydomonas reinhardtii is the active elimination of chloroplast DNA from the mating-type minus parent due presumably to the action of a zygote-specific nuclease. Meiotic progeny thus inherit chloroplast DNA almost exclusively from the mating-type plus parent. The plus-linked nuclear mutation mat3 prevents this selective destruction of minus chloroplast DNA and generates progeny that display a biparental inheritance pattern. Here we show that the mat3 mutation creates additional phenotypes not previously described: the cells are much smaller than wild type and they possess substantially reduced amounts of both mitochondrial and chloroplast DNA. We propose that the primary defect of the mat3 mutation is a disruption of cell-size control and that the inhibition of the uniparental transmission of chloroplast genomes is a secondary consequence of the reduced amount of chloroplast DNA in the mat3 parent.

Animals↗
PubMed2005

Golgi inheritance in mammalian cells is mediated through endoplasmic reticulum export activities.

Golgi inheritance during mammalian cell division occurs through the disassembly, partitioning, and reassembly of Golgi membranes. The mechanisms responsible for these processes are poorly understood. To address these mechanisms, we have examined the identity and dynamics of Golgi proteins within mitotic membranes using live cell imaging and electron microscopy techniques. Mitotic Golgi fragments, seen in prometaphase and telophase, were found to localize adjacent to endoplasmic reticulum (ER) export domains, and resident Golgi transmembrane proteins cycled rapidly into and out of these fragments. Golgi proteins within mitotic Golgi haze-seen during metaphase-were found to redistribute with ER markers into fragments when the ER was fragmented by ionomycin treatment. The temperature-sensitive misfolding mutant ts045VSVG protein, when localized to the Golgi at the start of mitosis, became trapped in the ER at the end of mitosis in cells shifted to 40 degrees C. Finally, reporters for Arf1 and Sar1 activity revealed that Arf1 and Sar1 undergo sequential inactivation during mitotic Golgi breakdown and sequential reactivation upon Golgi reassembly at the end of mitosis. Together, these findings support a model of mitotic Golgi inheritance that involves inhibition and subsequent reactivation of cellular activities controlling the cycling of Golgi components into and out of the ER.

ADP-Ribosylation Factor 1↗