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PubMed2006

First report of prevalence of non-syndromic hereditary prosopagnosia (HPA).

Acquired prosopagnosia (PA) is a rare condition after, for example, a stroke or brain injury. The congenital form of PA is generally considered to be even less common. Beside a few single case reports and anecdotal mentioning of familial cases no data on the epidemiology exists. Following a questionnaire-based screening in local secondary schools and at our medical faculty, candidates suspicious for PA underwent a semi-structured interview followed by examinations of first degree relatives. Among 689 local pupils and medical students of our university we found 17 with congenital PA. This corresponds to a prevalence rate of 2.47% (95% CI 1.31-3.63). The frequency is among the highest known for a monogenic disorder. All those index subjects (n = 14) of the target group who agreed to further examinations of their family members had other first degree relatives with the same cognitive disorder. This study provides epidemiological evidence that congenital PA is a very common cognitive disorder which almost always runs in families. The segregation pattern of this hereditary prosopagnosia (HPA) is fully compatible with autosomal dominant inheritance.

Family Health↗
PubMed2005

A genome-wide search for risk genes using homozygosity mapping and microarrays with 1,494 single-nucleotide polymorphisms in 22 eastern Cuban families with bipolar disorder.

Homozygosity mapping is a very powerful method for finding rare recessive disease genes in monogenic disorders and may also be useful for locating risk genes in complex disorders, late onset disorders where parents often are not available, and for rare phenotypic subgroups. In the present study, homozygosity mapping was applied to 24 persons with bipolar disorder from 22 inbred families. The families were selected irrespective of whether other affected family members were present or not. A genome wide screen using genotypes from only a single affected person in each family was performed using the AFFYMETRIX GeneChip HuSNP Mapping Assay, which contains 1,494 single nucleotide polymorphisms. At chromosome 17q24-q25 a parametric multipoint LOD score of 1.96 was found at WIAF-2407 and WIAF-2405. When analyzing 19 additional microsatellite markers on chromosome 17q the maximum parametric multipoint LOD score was 2.08, 1.5 cM proximal to D17S668. The present study replicates a recent significant linkage finding.

Alleles↗
PubMed2006

Haplotype-based systematic association studies of ATP1A2 in migraine with aura.

Mutations in ATP1A2 cause familial hemiplegic migraine (FHM) type 2, a rare monogenic form of migraine with aura (MA). Moreover, rare ATP1A2 missense variants are found in familial clustering of common forms of migraine in single pedigrees. To determine whether also common ATP1A2 polymorphisms contribute to MA pathogenesis, we performed systematic case-control association studies in 284 MA cases and 241 control individuals. By direct sequencing of the 23 coding exons and adjacent intronic regions in 45 MA patients, 16 polymorphisms (12 SNPs, 3 small indels, 1 microsatellite marker) were identified. The sequencing results were used to estimate seven common ATP1A2 haplotypes (with a frequency >5%) covering about 97% of total haplotype diversity for this region. Subsequently, six haplotype-tagging SNPs/polymorphisms were genotyped in 95 individuals with a family history of MA, in 189 individuals with sporadic MA, and in a gender-matched control sample. A haplotype analysis was performed using the program FAMHAP. No significant differences in the ATP1A2 haplotype distribution could be detected between MA patients (or patient subgroups) and the control group. In a single-marker analysis the allele and genotype frequencies of ATP1A2 polymorphisms between cases and controls were compared. Neither the six ht-SNPs nor a single allele of the microsatellite marker were significantly associated with MA. In summary, we found no evidence for a common contribution of ATP1A2 to the pathogenesis of complex inherited MA.

Adult↗
PubMed2007

Glutathione S-transferase polymorphisms and onset age in alpha-synuclein A53T mutant Parkinson's disease.

Monogenic forms of Parkinson's disease (PD) provide an opportunity to examine mechanisms underlying phenotypic variation. Glutathione S-transferase (GST) has detoxification and antioxidative functions. To screen genetic variations in GST for an effect on the onset age (OA) of PD, we typed seven common genetic polymorphisms in five GST isoenzymes, M1, M3, P1, T1, and Z1, in 36 affected individuals of Italian or Greek origin with the alpha-synuclein A53T (PARK1) mutation. Mean OA was 45.2 years with a wide SD of 11.03 years, similar to that of idiopathic PD. Our allelic analysis showed that the subjects homozygous for the GSTP1 G-for-A nucleotide substitution at position 313 had a mean OA acceleration of 15.2 years (31.3 +/- 7.09 years, n = 3 vs. 46.5 +/- 10.50 years, n = 33, P = 0.020). The GSTP1 C341T substitution was associated with a 9.7-year acceleration of OA, but the significance was borderline (36.4 +/- 8.35 years vs. 46.7 +/- 10.85 years, P = 0.0519). After correction for the five genes examined, both results lose statistical significance. Nevertheless, our results suggest that further investigation in GSTP1 variants and PD pathogenesis is warranted in sporadic PD and that a search for toxins that accelerate PD OA should pay particular attention to GST-P1 substrates.

Adenine↗
PubMed2004

Genomic imprinting and environment in hereditary paraganglioma.

Hereditary paraganglioma (PGL) is characterized by the development of slow-growing and vascularized tumors in the paraganglionic system. PGL is caused by germ line heterozygous inactivating mutations in the SDHB (PGL4), SDHC (PGL3), or SDHD (PGL1) genes, which encode three of the four subunits of mitochondrial complex II (succinate dehydrogenase; SDH). Common tumor sites include the carotid body in the neck and paraganglia in the abdomen. The risk of tumor development associated with SDHD mutations is determined by the sex of the transmitting parent, because only a paternal transmission leads to tumorigenesis in the progeny. This transmission pattern suggests operation of genomic imprinting on the SDHD gene. There is also evidence that the risk of tumor development increases at higher altitudes among SDHD mutation carriers. Accordingly, the increased prevalence of SDHD mutations in the Netherlands, attributable to multiple founder mutations, has been explained in part by the low altitudes in this country, which presumably reduce gene penetrance and relax the natural selection. Thus, PGL caused by SDHD mutations represents an unusual example of an inherited monogenic tumor syndrome because the risk of tumorigenesis shows an absolute dependence on the sex of the transmitting parent and may be modified by a ubiquitous environmental factor.

Atmospheric Pressure↗
PubMed1980

The inheritance of digital dermatoglyphic patterns in 54 American Caucasian families.

We searched for single gene effects in determining digital patterns and compared with the evidence for monogenic determination in Israelis (Slatis et al., '76). Our subjects were 108 parents from central Louisiana and 123 of their offspring; there were 127 females and 104 males ranging in age from eight to 66 years. Arches on the thumb--Among 11 subjects, two were bilateral, and three pairs were related, two as parent-child and one as sib-sib; the findings support the concept of an incompletely penetrant dominant gene. Radial loops on the thumb--three occurred unilaterally in unrelated subjects. Ulnar loops (U) and whorls (W) on the thumb--Phenotype frequency was 104 UU, 65 UW, 47 WW, 15 other. The proportion of UU offspring was highest with both UU parents and diminished as the parents had increasingly more W, supporting the single locus hypothesis. Arches (A) on the fingers--71 A, 160 non-A showed a greater A frequency than in the Israelis. The proportion of A offspring was highest with both A parents and diminished as the parents became non-A. Sequence WWUWW--Among nine subjects, one was bilateral, two left, and six right; two pairs related as parent-child and sib-sib. Sequence WUUWW--Among five subjects, one was bilateral, and three were related as parent-offspring. Radial loops on index fingers--Frequency of 32% was greater than in the Israelis. Middle fingers--86% were U, 73% being bilateral. Radial loops on ring and little fingers--Among eight unilateral subjects, none was related. Ulnar loops and whorls on ring fingers--Proportion of UU offspring was greatest with both UU parents and diminished as parents became WW. We conclude that the Louisianians showed evidence for single gene effects similar to that of the Israelis.

Adolescent↗
PubMed1987

Partial correlation of distance matrices in studies of population structure.

Anthropological studies of human population structure commonly compare various monogenic and polygenic (metric) distance matrices to distance matrices obtained from measures of geographical dispersion, linguistic differences, and migration patterns in an attempt to infer something about the effects of evolutionary factors (drift and differential selection, in particular). It is, though, commonly recognized that geography, language, and migration patterns may be intercorrelated due to the common effects of historical and social processes. Previous attempts to deal with the problems of assessing relative effects among such sets of intercorrelated factors using partial correlations have resulted in coefficients that are either not well defined or have no known sampling distribution or both. Here, we outline a general approach to partialling distance matrices that results in well-defined coefficients and valid significance testing procedures. Application of the matrix partialling methods to a variety of distance matrices obtained for a sample of eight ethnolinguistic groups from the Harvard Solomon Islands Expedition (Friedlaender et al., 1986) reveals a close association between language dissimilarity and dermatoglyphics controlling for geography, thus reinforcing earlier suggestions that dermatoglyphics, properly used, reflect historical relationships of groups in this region better than do anthropometry, odontometrics, or small batteries of blood polymorphisms.

Anthropology↗
PubMed2002

A nonsense mutation of the MASS1 gene in a family with febrile and afebrile seizures.

A naturally occurring mutation of the mass1 (monogenic audiogenic seizure-susceptible) gene recently has been reported in the Frings mouse strain, which is prone to audiogenic seizures. The human orthologous gene, MASS1, was mapped to chromosome 5q14, for which we previously have reported significant evidence of linkage to febrile seizures (FEB4). We screened for MASS1 mutations in individuals from 48 families with familial febrile seizures and found 25 DNA alterations. None of nine missense polymorphic alleles was significantly associated with febrile seizures; however, a nonsense mutation (S2652X) causing a deletion of the C-terminal 126 amino acid residues was identified in one family with febrile and afebrile seizures. Our results suggest that a loss-of-function mutation in MASS1 might be responsible for the seizure phenotypes, though it is not likely that MASS1 contributed to the cause of febrile seizures in most of our families.

Base Sequence↗
PubMed1984

The new wave of research in the epilepsies.

In addition to yielding new routes of navigation, the workshops from which the material in this supplement comes developed a conceptual blueprint for priority challenges in epilepsy research. All participants called attention to the ultimate goal, namely, understanding the mechanisms of human epilepsies. And, foremost to achieving this goal is the search for polymorphisms of restriction endonuclease patterns in monogenic forms of epilepsies in an attempt to localize the abnormal gene, or genes, to a specific chromosome. In human temporal lobe epilepsy, a priority challenge is to record paroxysmal depolarization shifts in hippocampal slices in vitro, slices excised from the known site of epileptogenicity. Parallel experiments exploring biochemical membrane abnormalities in neuronal and glial membranes isolated from the hippocampal seizure focus are especially valuable. Together with genetic studies using restriction-fragment-length polymorphisms, these experiments should distinguish between the respective contributions of genetic and environmental factors in multifactorial forms of partial epilepsies, such as temporal lobe epilepsy. In the genesis and spread of human temporal lobe epilepsy, the role of kindling and the mirror focus must be resolved. Recent successful applications of positron emission tomography, single-photon-emission computed tomography, and nuclear magnetic resonance computed tomography show promise in finally constructing the ion transport pathways, neurotransmitter systems, and metabolic processes within the functioning brains of epileptic patients.

Animals↗
PubMed1991

Autosomal dominant arthropathy in a French family.

We studied a French family in which 18 adult members had destructive arthropathy and enthesopathic changes. In 16 patients, the diagnosis was verified radiologically, and in the 2 other patients, the clinical history was consistent with familial arthropathy. The disease predominantly affects the wrists, fingers, shoulders, and peripheral entheses, and its onset occurs after age 18. Genetic transmission is autosomal dominant, with 100% penetrance, and is not related to the HLA system. The clinical and radiologic features are strikingly similar in all patients in successive generations and different branches of the genealogic tree, and this suggests monogenic transmission.

Age Factors↗
PubMed2006

Ectopic calcification among families in the Azores: clinical and radiologic manifestations in families with diffuse idiopathic skeletal hyperostosis and chondrocalcinosis.

OBJECTIVE: Twelve families that were multiply affected with diffuse idiopathic skeletal hyperostosis (DISH) and/or chondrocalcinosis, were identified on the island of Terceira, The Azores, potentially supporting the hypothesis that the 2 disorders share common etiopathogenic factors. The present study was undertaken to investigate this hypothesis. METHODS: One hundred three individuals from 12 unrelated families were assessed. Probands were identified from patients attending the Rheumatic Diseases Clinic, Hospital de Santo Espírito, in The Azores. Family members were assessed by rheumatologists and radiologists. Radiographs of all family members were obtained, including radiographs of the dorsolumbar spine, pelvis, knees, elbows, and wrists, and all cases were screened for known features of chondrocalcinosis. RESULTS: Ectopic calcifications were identified in 70 patients. The most frequent symptoms or findings were as follows: axial pain, elbow, knee and metacarpophalangeal (MCP) joint pain, swelling, and/or deformity, and radiographic enthesopathic changes. Elbow and MCP joint periarticular calcifications were observed in 35 and 5 patients, respectively, and chondrocalcinosis was identified in 12 patients. Fifteen patients had sacroiliac disease (ankylosis or sclerosis) on computed tomography scans. Fifty-two patients could be classified as having definite (17%), probable (26%), or possible (31%) DISH. Concomitant DISH and chondrocalcinosis was diagnosed in 12 patients. Pyrophosphate crystals were identified from knee effusions in 13 patients. The pattern of disease transmission was compatible with an autosomal-dominant monogenic disease. The mean age at which symptoms developed was 38 years. CONCLUSION: These families may represent a familial type of pyrophosphate arthropathy with a phenotype that includes peripheral and axial enthesopathic calcifications. The concurrence of DISH and chondrocalcinosis suggests a shared pathogenic mechanism in the 2 conditions.

Adult↗
PubMed2025

Diagnostic Implications and Correlates of Plasma Adenosine Deaminase 2 Activity and ADA2 Variants.

OBJECTIVE: Deficiency of adenosine deaminase 2 (DADA2) is a monogenic autoinflammatory disease manifested as polyarteritis nodosa, stroke, and bone marrow failure. Leveraging an international cohort of 200 DADA2 cases, we aimed to characterize the diagnostic utility of a plasma ADA2 enzyme activity assay and understand the implications of residual ADA2 activity. METHODS: Data were collected from individuals who underwent ADA2 testing from 2018 to 2025. Plasma ADA2 activity was determined using an established spectrophotometric assay. ADA2 variants were analyzed in transfected cells by enzyme assay and western blotting. RESULTS: We determined that plasma ADA2 activity is 99.0% and 96.0% sensitive and 99.7% and 98.8% specific in distinguishing genetically confirmed DADA2 cases from controls and carriers, respectively. Eighteen individuals with DADA2 (9%) possessed detectable ADA2 activity, including several cases with levels seen in carriers. Residual ADA2 activity was associated with the vasculitis/inflammatory phenotype but not with disease severity. Genotype analysis revealed that 14 of 18 cases with residual plasma activity possessed at least one hypomorphic missense variant with greater than 20% residual ADA2 function when overexpressed in 293T cells, often occurring in trans with a more deleterious variant. In vitro analysis revealed that missense ADA2 variants exert variable dominant-negative effects by forming large intracellular protein aggregates via disulfide bond formation at a cysteine residue (Cys408). CONCLUSION: We confirmed the utility of plasma ADA2 activity as a diagnostic assay and showed that the inflammatory phenotype of DADA2 occurred in cases with residual activity. In vitro findings illustrate potential interactions of ADA2 variants to synergistically disrupt protein function.

Humans↗
PubMed2006

Clomiphene and hypospadias on a detailed level: signal or chance?

BACKGROUND: Clomiphene, a drug used to induce ovulation, is chemically related to diethylstilbestrol (DES). DES is associated with vaginal cancer and infertility among daughters and with hypospadias among second-generation male offspring. Because clomiphene has a long half-life and metabolites have been found in feces up to 6 weeks after administration, fetal exposure is possible if the mother took this drug prior to becoming pregnant. METHODS: Case-control analyses were performed to investigate the association between clomiphene exposure and hypospadias. Cases were all male subjects registered in the European Concerted Action on Congenital Anomalies and Twins (EUROCAT) Northern Netherlands registry for congenital anomalies with nonsyndromal hypospadias. Controls were all male children born without hypospadias, including those with chromosomal and monogenic defects. Logistic regression analyses were performed to calculate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Of 392 cases, 7 (1.8%) were exposed to clomiphene compared with 64 of 4538 controls (1.4%). For penoscrotal hypospadias, we found that the OR was significantly increased (6.08; 95% CI, 1.40-26.33); for the mild and moderate forms of hypospadias, the ORs were not increased. CONCLUSIONS: Because penoscrotal hypospadias is rare, the effect is diluted when all forms of hypospadias are studied as a group. Therefore, our study stresses the importance of studying birth defects on as detailed a level as possible. Other studies should be conducted to confirm our findings.

Abortion, Induced↗
PubMed2003

The MID1/PP2A complex: a key to the pathogenesis of Opitz BBB/G syndrome.

Opitz BBB/G syndrome is a monogenic disorder that is characterized by malformations of the ventral midline. Investigations into the underlying genetic defects and the pathobiochemistry of this syndrome have already shed light on the mechanisms of both the physiological and the pathological development of the ventral midline, a complicated multistep process. Moreover, these studies have revealed the ubiquitin-dependent regulation of microtubule-associated phosphatase 2A, a central mechanism in many cellular processes. In this review, we summarize recent findings and speculate upon their implications for both medical and general research.

Abnormalities, Multiple↗
PubMed2006

Ontogeny of ingestive behavior.

Review of the ontogeny of the controls of independent ingestion reveals that some of the direct and indirect controls of meal size identified in adult rats function in the first three postnatal weeks. The controls appear sequentially and some of them change their potency after they emerge. Indirect controls exerted by metabolism and adiposity do not emerge until the fourth postnatal week or later in the postweaning period. Recent experiments in rats with monogenic obesities involving the leptin and cholecystokinin receptors have demonstrated the usefulness of independent ingestion in the detection of the earliest expression of hyperphagia. Although much remains to be learned about the normal controls of independent ingestion, it is clear that it provides relevant information about the development of normal and abnormal controls of meal size in rodents that is useful for translational research into the controls of meal size in normal and obese children.

Animals↗
PubMed2004

A new murine model of humoral immuno-deficiency specifically affects class switching to T-independent antigens.

Immunoglobulin (Ig) isotype deficiencies are among the most common and least characterized humoral immunodeficiencies. A thorough understanding of their immunological and genetic features has been hampered by their extreme heterogeneity and the paucity of suitable animal models. Here, we report the initial characterization of a new mouse model with selective Ig deficiency. SENCARA mice display low serum IgG3 levels as well as severely deficient IgG3 responses to T cell-independent (TI) type 1 and 2 antigens. However, despite the significant block in class switching, expression of activation-induced deaminase and gamma3 germ-line transcription after TI antigen immunization are normal. IgG3 production in response to in vitro LPS stimulation was also normal, ruling out a specific defect in the Cgamma3 switch machinery. A decrease in the number of peritoneal B1a cells and enlarged splenic marginal zones were observed. The immunodeficiency is inherited as an autosomal, semi-dominant, essentially monogenic trait in SENCARA x C57BL/6 crosses. The SENCARA humoral immunodeficiency constitutes a novel immune phenotype, resembling human conditions such as IgG2 deficiency. This new mouse model will be of interest for the understanding of mechanisms involved in TI immune responses and may provide new insights into the molecular basis of human Ig deficiencies.

Animals↗
PubMed2007

Genetic analysis of the innate immune responses in wild-derived inbred strains of mice.

The vertebrate immune system has evolved to recognize nucleic acids of bacterial and viral origin. Microbial DNA, as well as synthetic oligonucleotides based on these motifs, activates innate immune pathways mediated by the family of Toll-like receptors (TLR) initiating a cascade of signals in immune cells necessary for responses to pathogens. However, not all of the proteins that participate in TLR-mediated responses have been identified. In studies described herein, we observed significant variation in innate immune responses among selected wild-derived strains of mice. Specifically, we show that mice of MOLF/Ei, Czech/Ei, and MSM/Ms strains are hypo-responsive to polyinosinic-polycytidylic acid (poly(I:C)) because of a mutation in Tlr3. In addition, we discovered a hypo-response to cytosine guanine dinucleotide in MOLF/Ei mice and established that it is not linked to Tlr9, but to another locus. Further inquiry revealed that this hypo-response is transmitted as a monogenic dominant trait that can be mapped and cloned through positional cloning methods. These results suggest the existence of a novel molecule that can alter pro-inflammatory signals or activate additional signal transduction pathways. In addition, they support the wild-derived mouse strain as a forward genetic tool for the identification of novel immunological phenotypes.

Amino Acid Sequence↗
PubMed1990

Inbred testing of tomato (Lycopersicon esculentum L.) F1 varieties by ultrathin-layer isoelectric focusing of seed protein.

To test seed lots of tomato F1 hybrid varieties for the presence of undesirable inbred seeds by electrophoresis, a method has been developed on the basis of ultrathin-layer isoelectric focusing. The method is based on the genetic variation of the seed protein PRS-1 which could be visualized by isoelectric focusing of a 5 mM NaCl-soluble seed protein extract in a pH 6-9 gel followed by protein staining. Two genetic variants of the PRS-1 protein, PRS-1+ and PRS-1(1), were found among open-pollinated varieties, as well as among F1 hybrid varieties. The isoelectric points (pI) of the PRS-1 proteins are 7.1 and 6.1 for PRS-1+ and PRS-1(1), respectively. The PRS-1 protein is unique to seed tissue and is located primarily in the embryo. A genetic 1:2:1 segregation of the gene Prs-1 among several F2 populations shows monogenic inheritance. Analysis of commercial F1 hybrid varieties from several seed companies indicated that the Prs-1(1) allele, in contrast to the Prs-1+ allele, is primarily present in gene pools of "Money-maker type" tomatoes. The described method is generally applicable to all tomato F1 varieties that are heterozygous for the gene Prs-1. With the described method one person can routinely analyze more than 768 seeds per day.

Alleles↗