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PubMed1984

Disseminated hereditary gastrointestinal polyposis with orocutaneous hamartomatosis (Cowden's disease).

Cowden's disease, first described by Lloyd and Dennis in 1962, is a rare disseminated polyposis of the gastrointestinal tract with an autosomal dominant inheritance pattern, infrequently cited in the contemporary gastroenterological literature. In addition to multiple polyps, which are scattered throughout the gastrointestinal tract from the mouth to the anus, orocutaneous hamartomas and frequent benign and malignant cutaneous, thyroid and breast tumors are thought to represent the most common manifestations of the disease. Ectodermal lesions are most frequently reported as a salient feature, and represent the most consistent element in the definition of this condition in the majority of cases, most of which are recorded in the dermatological literature (multiple hamartoma syndrome or Cowden's disease). This article presents four cases of Cowden's disease, the patients being members of two genetically unrelated families. All four patients had disseminated polyposis of the gastrointestinal tract, extending from the oral mucosa to the anus, while the cutaneous lesions and the concomitant tumors were present either in a fully developed or only rudimentary form, or were even absent. The authors propose that the term "disseminated hereditary gastrointestinal polyposis with orocutaneous hamartomatosis " be introduced and consistently used in the gastroenterological literature when referring to Cowden's disease, which seems more common than previous reports in the literature would indicate.

Adult↗
PubMed1980

[Autosomal dominant mild juvenile diabetes mellitus (MODY) (author's transl)].

A family is described in which eleven members, over four generations, suffer from the autosomal dominant inherited maturity onset type diabetes of young people (MODY). A comparison of these findings with those of six families previously described in the literature shows in particular that: 1. manifestation of the disease is predominantly at a fairly young age, 2. the complaint is not insulin-dependent nor is it progressive, 3. when medical supervision is adequate, there are hardly any secondary complications, 4. the inheritance pattern is autosomal dominant with high penetrance and probably a stronger expressivity in the female. This disease can be separated from the classical, insulin-dependent diabetes of the young, from the autosomal dominant lipatrophic diabetes and from the heterozygous form of the autosomal recessive complaint, which in the homozygous state shows diabetes mellitus and insipidus with optic atrophy.

Adolescent↗
PubMed1991

Familial aspects of Hirschsprung's disease.

Twenty-eight of 370 patients (14 families) treated for Hirschsprung's disease (HD) over a 34 year period had a family member with histologically proven HD. These 14 represented 4% of the 351 families: more than one affected child per family in 10 (2.8%) and both parent and child in 2 families. Neuronal intestinal dysplasia (NID) in a parent was associated with total colonic aganglionosis in two siblings of one family which suggests a similar genetic inheritance pattern to HD. Aganglionosis extended beyond the rectosigmoid in 61% of the familial group as opposed to 27% of the non-familial group. A significantly higher number of total colonic aganglionosis (TCA) was noted in those with a family history; 11 out of 28 (39%) as opposed to 19 out of 342 (5.6%) without a family history (p less than 0.001). Fifty percent of males with TCA had a family history but in only 2 cases was this transmitted through a female sibling. Although no significant difference was noted between male and female probands, a three times higher incidence of familial occurrence was noted in females with rectosigmoid disease than in males. Progression of length of segment in succeeding generations was noted in two families. Associated anomalies occurred in 16% without familial occurrence and 11% of the familial group.

Adult↗
PubMed1977

Spinocerebellar ataxia and HLA linkage: risk prediction by HLA typing.

To determine the possibility of genetic linkage of spinocerebellar ataxia with the histocompatibility loci, we performed HLA typing and linkage analysis on 19 members of a kindred in which spinocerebellar ataxia was segregating in an autosomal dominant inheritance pattern. The ataxia locus was located on chromosome 6 at 12-cM distance from the HLA complex with lod score of 3.15 (odds is greater than 1400:1 favoring linkage over chance findings). Thus, the presence of the ataxia gene in members of this kindred at risk can be predicted with about 90 per cent accuracy by means of HLA typing in informative matings.

Cerebellar Ataxia↗
PubMed2001

Familial cold autoinflammatory syndrome: phenotype and genotype of an autosomal dominant periodic fever.

BACKGROUND: Familial cold autoinflammatory syndrome (FCAS), commonly known as familial cold urticaria, is a rare autosomal dominant inflammatory disorder with episodic symptoms precipitated by exposure to cold. OBJECTIVE: The goal of this study was to formulate clinical diagnostic criteria for FCAS in a large cohort in whom the diagnosis of FCAS was supported by genetic linkage to chromosome 1q44. METHODS: We assessed 45 affected and 68 unaffected members from 6 American families. DNA analysis was performed to confirm linkage to chromosome 1q44. Clinical characteristics were determined by means of analysis of detailed questionnaires and medical histories. RESULTS: Pedigree and genetic analyses confirmed autosomal dominant transmission and linkage to chromosome 1q44 in all families. The most consistent symptoms during attacks were rash (100%), fever (93%), arthralgia (96%), and conjunctivitis (84%). Age of onset was within the first 6 months of life in 95% of affected subjects. The average delay between cold exposure and onset of symptoms was 2.5 hours, and the average duration of an episode was 12 hours. Renal disease with amyloidosis occurs infrequently in FCAS (2%). CONCLUSION: The most consistent clinical characteristics of FCAS that discriminate it from other periodic fevers are association with cold exposure, conjunctivitis, age of onset, duration of episodes, and an autosomal dominant inheritance pattern. On the basis of the analysis of genotype and phenotype of FCAS, we formulated clinical diagnostic criteria that can be used to distinguish FCAS from other hereditary periodic fever syndromes.

Adolescent↗
PubMed2003

Multiple recurrent and de novo odontogenic keratocysts associated with oral-facial-digital syndrome.

In 1954, Papillon-Leage and Psaume were the first to describe the clinical characteristics of oral-facial-digital syndrome (OFDS). On the basis of their clinical features and the inheritance pattern, 2 variants were initially distinguished, namely OFDS type I (Papillon-Leage and Psaume) and OFDS type II, or Mohr syndrome. At present, 11 types of OFDS have been discovered. OFDS represents a heterogeneous group of disorders characterized by oral manifestations including oral frenula, cleft or lobulated tongue, high arched palate, cleft lip and/or palate, facial anomalies, and digital abnormalities such as syndactyly, polydactyly, brachydactyly, and clinodactyly. Depending on the type of OFDS, abnormalities may be present in other organs, such as the brain and heart. We report a patient with OFDS in whom multiple recurrent and de novo keratocysts were found. Although multiple keratocysts are commonly found in Gorlin-Goltz nevoid basal cell carcinoma syndrome, a relationship between OFDS and multiple keratocysts has not been described.

Child↗
PubMed2003

Birt-Hogg-Dubé syndrome: a review of the literature and the differential diagnosis of firm facial papules.

Birt-Hogg-Dubé syndrome (BHDS) was originally described in 1977 as the grouping of 3 skin tumors-the fibrofolliculoma, trichodiscoma, and acrochordon-in family members with an autosomal dominant inheritance pattern. In recent years it has become clear that these 3 lesions likely represent only 1 of these tumors, the fibrofolliculoma. More important, evidence now supports a definite susceptibility to malignant renal tumors and pulmonary disease in patients with BHDS. Clinical recognition of this entity is possible in spite of the fact that several syndromes exist that are characterized by the presence of multiple firm facial papules. We will discuss the evolution of BHDS from the original description to the recent discovery of the genetic susceptibility locus, illustrate the clinical differential diagnosis, and highlight the workup needed for newly diagnosed patients and their family members.

Diagnosis, Differential↗
PubMed2006

Meat and Livestock Association Plenary Lecture 2005. Oocyte signalling molecules and their effects on reproduction in ruminants.

Sheep (Ovis aries) are a highly diverse species, with more than 900 different breeds that vary significantly in their physiological characteristics, including ovulation rate and fecundity. From examination of inherited patterns of ovulation rate, several breeds have been identified with point mutations in two growth factor genes that are expressed in oocytes. Currently, five different point mutations have been identified in the BMP15 (GDF9b) gene and one in GDF9. Animals heterozygous for the GDF9 and/or the BMP15 mutations have higher ovulation rates than their wild-type counterparts. In contrast, those homozygous for any of the aforementioned BMP15 or GDF9 mutations are sterile owing to arrested follicular development. In bovine and ovine ovaries, GDF9 was expressed exclusively in oocytes throughout follicular growth from the primordial stage of development, whereas in sheep BMP15 was expressed exclusively in oocytes from the primary stage: no data for the ontogeny of BMP15 expression are currently available for cattle. In vitro, ovine growth differentiation factor 9 (oGDF9) has no effect on (3)H-thymidine incorporation by either bovine or ovine granulosa cells, whereas ovine bone morphogenetic protein 15 (oBMP15) has modest (1.2- to 1.6-fold; P < 0.05) stimulatory effects. Ovine GDF9 or oBMP15 alone inhibited progesterone production by bovine granulosa cells, whereas in ovine cells only oGDF9 was inhibitory. The effects of oGDF9 and oBMP15 together were often cooperative and not always the same as those observed for each factor alone. Active immunisation of ewes with BMP15 and/or GDF9 peptides affected ovarian follicular development and ovulation rate. Depending on the GDF9 and/or BMP15 vaccine formulation, ovulation rate was either increased or suppressed. A primary and single booster immunisation of ewes with a BMP15 peptide in a water-based adjuvant has led to 19-40% increases in lambs born per ewe lambing. Collectively, the evidence suggests that oocyte signalling molecules have profound effects on reproduction in mammals, including rodents, humans and ruminants. Moreover, in vivo manipulation of these oocyte signalling molecules provides new opportunities for the management of the fertility of ruminants.

Animals↗
PubMed2004

Susceptibility to astrocytoma in mice mutant for Nf1 and Trp53 is linked to chromosome 11 and subject to epigenetic effects.

Astrocytoma is the most common malignant brain tumor in humans. Loss of the p53 signaling pathway and up-regulation of the ras signaling pathway are common during tumor progression. We have shown previously that mice mutant for Trp53 and Nf1 develop astrocytoma, progressing to glioblastoma, on a C57BL/6J strain background. In contrast, here we present data that mice mutant for Trp53 and Nf1 on a 129S4/SvJae background are highly resistant to developing astrocytoma. Through analysis of F1 progeny, we demonstrate that susceptibility to astrocytoma is linked to chromosome 11, and that the modifier gene(s) responsible for differences in susceptibility is closely linked to Nf1 and Trp53. Furthermore, this modifier of astrocytoma susceptibility is itself epigenetically modified. These data demonstrate that epigenetic effects can have a strong effect on whether cancer develops in the context of mutant ras signaling and mutant p53, and that this mouse model of astrocytoma can be used to identify modifier phenotypes with complex inheritance patterns that would be unidentifiable in humans. Because analysis of gene function in the mouse is often performed on a mixed C57BL/6,129 strain background, these data also provide a powerful example of the potential of these strains to mask interesting gene functions.

Animals↗
PubMed2004

Linkage analysis of ordinal traits for pedigree data.

Linkage analysis is used routinely to map genes for human diseases and conditions. However, the existing linkage-analysis methods require that the diseases or conditions either be dichotomized or measured by a quantitative trait, such as blood pressure for hypertension. In the latter case, normality is generally assumed for the trait. However, many diseases and conditions, such as cancer and mental and behavioral conditions, are rated on ordinal scales. The objective of this study was to establish a framework to conduct linkage analysis for ordinal traits. We propose a latent-variable, proportional-odds logistic model that relates inheritance patterns to the distribution of the ordinal trait. We use the likelihood-ratio test for testing evidence of linkage. By means of simulation studies, we find that the power of our proposed model is substantially higher than that of the binary-trait-based linkage analysis and that our test statistic is robust with regard to certain parameter misspecifications. By using our proposed method, we performed a genome scan of the hoarding phenotype in a data set with 53 nuclear families, which were collected by the Tourette Syndrome Association International Consortium for Genetics (TSAICG). Standard linkage scans using hoarding as a dichotomous trait were also performed by using GENEHUNTER and ALLEGRO. Both GENEHUNTER and ALLEGRO failed to reveal any marker significantly linked to the binary hoarding phenotypes. However, our method identified three markers at 4q34-35 (P = 0.0009), 5q35.2-35.3 (P = 0.0001), and 17q25 (P = 0.0005) that manifest significant allele sharing.

Genetic Linkage↗
PubMed2006

The callipyge mutation enhances bidirectional long-range DLK1-GTL2 intergenic transcription in cis.

The callipyge mutation (CLPG) is an A to G transition that affects a muscle-specific long-range control element located in the middle of the 90-kb DLK1-GTL2 intergenic (IG) region. It causes ectopic expression of a 327-kb cluster of imprinted genes in skeletal muscle, resulting in the callipyge muscular hypertrophy and its non-Mendelian inheritance pattern known as polar overdominance. We herein demonstrate that the CLPG mutation alters the muscular epigenotype of the DLK1-GTL2 IG region in cis, including hypomethylation, acquisition of novel DNase-I hypersentivite sites, and, most strikingly, strongly enhanced bidirectional, long-range IG transcription. The callipyge phenotype thus emerges as a unique model to study the functional significance of IG transcription, which recently has proven to be a widespread, yet elusive, feature of the mammalian genome.

Alleles↗
PubMed2000

Pseudoxanthoma elasticum: mutations in the MRP6 gene encoding a transmembrane ATP-binding cassette (ABC) transporter.

Pseudoxanthoma elasticum (PXE), the prototypic heritable connective tissue disorder affecting the elastic structures in the body, manifests with cutaneous, ophthalmologic, and cardiovascular findings, with considerable morbidity and mortality. The molecular basis of PXE has remained unknown, but the disease locus has recently been mapped to an approximately 500-kb interval on chromosome 16p13.1, without evidence for locus heterogeneity. In this study, we report pathogenetic mutations in MRP6, a member of the ABC transporter gene family, in eight kindreds with PXE. The mutation detection strategy consisted of heteroduplex scanning of coding sequences in the MRP6 gene, which were amplified by PCR by using genomic DNA as template, followed by direct nucleotide sequencing. A total of 13 mutant MRP6 alleles were disclosed in the eight probands with PXE. These genetic lesions consisted of either single base pair substitutions resulting in missense, nonsense, or splice site mutations, or large deletions resulting in allelic loss of the MRP6 locus. Examination of clinically unaffected family members in four multiplex families identified heterozygous carriers, consistent with an autosomal recessive inheritance pattern. Collectively, identification of mutations in the MRP6 gene provides the basis to examine the pathomechanisms of PXE and allows development of DNA-based carrier detection, prenatal testing, and preimplantation genetic diagnosis in families with a history of this disease.

ATP-Binding Cassette Transporters↗
PubMed1970

A Saccharomyces cerevisiae mutant defective in saturated fatty acid biosynthesis.

The isolation and biochemical characterization of a Saccharomyces cerevisiae mutant, which grows only when emulsified myristic, palmitic, stearic, or oleic acid is added to the growth medium, is described. The mutant contains an enzymatically inactive fatty acid synthetase complex. The gene affected, preliminarily designated by the symbol fas, exhibits a 2:2 nuclear inheritance pattern. The formation of fatty acid synthetase in yeast is constitutive and not subject to repression by long chain fatty acids. After extensive purification, the mutant fatty acid synthetase was obtained as an essentially homogeneous protein with a sedimentation constant identical to that of the wild type enzyme. A systematic study of the seven reaction steps involved in fatty acid biosynthesis revealed that the enzyme catalyzing the condensation of acetate and malonate to acetoacetate was completely inactive in the mutant. The other six component enzymes had identical specific activities in the mutant and in the wild type fatty acid synthetase complexes. It is concluded that the mutant described harbors a missense mutation in the structural genes of either the condensing enzyme of the "acyl carrier protein" component of the fatty acid synthetase complex.

Depression, Chemical↗
PubMed1975

Specific human B lymphocyte alloantigens linked to HL-A.

Sera, previously found to react specifically with B lymphoid cultured cells, were tested on isolated T and B peripheral blood lymphocytes in a microcytotoxicity assay. Studies were performed on lymphocytes obtained from several large Amish families. The sera used in these studies were cytotoxic to peripheral blood, B lymphocytes, but not cytotoxic to T lymphocytes. The antigens detected followed the inheritance pattern of HL-A haplotypes. The strong linkage disequilibrium with HL-A antigens suggests that genes controlling the expression of B lymphocyte antigens are linked to genes controlling HL-A alloantigens.

B-Lymphocytes↗
PubMed1979

Neodymium isotopes in flood basalts from the Siberian Platform and inferences about their mantle sources.

The initial isotopic compositions of Nd and Sr in basalts from the Central Siberian Plateau and other major continental flood basalts are reported. The continental flood basalts appear to be the product of partial melting of mantle sources that consist of relatively primitive undifferentiated material and are clearly distinct from midocean ridge basalts, which sample mantle reservoirs that have been modified by extraction of continental crust earlier in earth history. These observations provide fundamental constraints on models of mantle structure and dynamics. Isotopic effects of crustal contamination are clearly recognizable in some continental flood basalts, but these effects can be distinguished from isotopic patterns inherited from the mantle magma sources.

Journal Article↗
PubMed1988

Genetic deficiency of the alpha subunit of the guanine nucleotide-binding protein Gs as the molecular basis for Albright hereditary osteodystrophy.

Patients who have pseudohypoparathyroidism type I associated with Albright hereditary osteodystrophy commonly have a genetic deficiency of the alpha subunit of the G protein that stimulates adenylyl cyclase (alpha Gs) (ATP pyrophosphate-lyase, EC 4.6.1.1). To discover the molecular mechanism that causes alpha Gs deficiency in these patients, we examined eight kindreds with one or more members affected with Albright hereditary osteodystrophy or pseudohypoparathyroidism and alpha Gs deficiency. In these families, alpha Gs deficiency and the Albright hereditary osteodystrophy phenotype were transmitted together in a dominant inheritance pattern. Using a cDNA hybridization probe for alpha Gs, restriction analysis with several endonucleases showed no abnormalities of restriction fragments or gene dosage. RNA blot and dot blot analysis of total RNA from cultured fibroblasts obtained from the patients revealed approximately equal to 50% reduced mRNA levels for alpha Gs in affected members of six of the pedigrees but normal levels in affected members of the two other pedigrees, compared to mRNA levels in fibroblasts from unaffected individuals. By contrast, mRNA levels encoding the alpha subunit of the G protein that inhibits adenylyl cyclase were not altered. Our findings suggest that several molecular mechanisms produce alpha Gs deficiency in patients with pseudohypoparathyroidism type Ia and that major gene rearrangements or deletions are not a common cause for alpha Gs deficiency in pseudohypoparathyroidism type I.

Cell Membrane↗
PubMed1988

Characterization of a genomic hybrid specifying the human erythrocyte antigen Dantu: Dantu gene is duplicated and linked to a delta glycophorin gene deletion.

Dantu is a rare antigen of the human MNSs blood group system carried by a hybrid glycophorin on the erythrocyte membrane. To delineate its structure and relationship to alpha and delta glycophorins at the genomic level, we analyzed DNA from a three-generation family, in which both the presence of Dantu and Mi-III (another rare MNSs antigen) and the absence of delta glycophorin were seen. Three gross alterations in the gene cluster correlated with the observed phenotypes. Differential hybridization, secondary restriction analysis, and sequence-specific oligonucleotide probing established that Dantu glycophorin is encoded by a distinct hybrid gene derived from fusion of delta and alpha genes. The junction point of the Dantu gene was assigned to the region spanning codons 31-39 of delta and codons 72-79 of alpha genes. Dosage quantitation suggested that Dantu gene is duplicated and tandemly arranged. Identification of delta gene deletion disclosed the molecular basis for the absence of delta glycophorin in two Dantu and Mi-III double heterozygotes. The DNA inheritance pattern together with DNA typing of MN blood groups verified the genotypes and established that the duplicated Dantu hybrid gene is linked to alpha M gene as well as a delta gene deletion. The origin of such a haplotype in a segment of Black population would require two recombination events via either unequal homologous crossing-over or gene conversion.

Base Sequence↗