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PubMed1998

HLA-DP: a class II restriction molecule involved in epitope spreading during the development of multiple sclerosis.

Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system. It is widely believed that complex polygenic inheritance patterns involving HLA-DR and -DQ class II genes contribute to MS susceptibility, and current evidence indicates that disease risk vs disease outcome may be associated with distinctly different HLA class II alleles. We have recently shown that the early development of MS is accompanied by an extensive plasticity of myelin self-recognition with the acquisition of neo-autoreactivity, or epitope spreading, as a prominent feature. Although we did not observe a common determinant recognized by patients sharing identical HLA-DR or -DQ class II alleles, we did observe epitope spreading to the p50-63 determinant of myelin proteolipid protein (PLP) in two study subjects showing complete disparity at HLA-DR and -DQ but identity at the HLA-DP allele DPB1*0301. In the present study we show that self-recognition during the early stages in the development of MS involves HLA-DP class II restricted responses to the PLP 50-63 spreading determinant. Our results suggest that self-presentation by HLA-DP may play an important role in epitope spreading and in the propagation of self-recognition during the clinical progression of MS.

Adult↗

PubMed1995

Familial congenital pseudarthrosis of the ulna.

A mother and daughter, both presented with congenital pseudarthrosis of the ulna due to neurofibromatosis. The daughter is one of identical twins, the second twin not having a pseudarthrosis. The mother's uncle also had pseudarthrosis of the tibia. This suggests a complex variable genetic inheritance pattern for pseudarthrosis in neurofibromatosis. Despite having had no treatment, the mother had minimal symptoms, minimal deformity, and no radial head dislocation.

Child, Preschool↗

PubMed2001

Identification of a novel form of renal glucosuria with overexcretion of arginine, carnosine, and taurine.

Glucosuria occurs in diabetes mellitus, generalized proximal tubular dysfunction of Fanconi's syndrome, glucose-galactose malabsorption syndrome, and primary renal glucosuria. Patients with primary renal glucosuria have normal blood glucose levels, normal oral glucose tolerance test results, and persistent glucosuria that may approach the filtered load of glucose in the most severe cases. The primary defect is proposed to be in the sodium-glucose cotransporter type-2 (SGLT2) located in the apical membrane of S1 segment proximal renal tubule cells. Primary renal glucosuria is classified as types A, B, or O based on the characteristics of the transport defect. The magnitude of glucosuria has varied from 20 to 150 g of glucose excreted in 24 hours. Described inheritance patterns have included both autosomal dominant and autosomal recessive mechanisms. Some cases have been associated with selective aminoaciduria, distinctly unlike the generalized aminoaciduria seen in Fanconi's syndrome. We report the first case of primary renal glucosuria with selective overexcretion of arginine, carnosine, and taurine. This case may represent a genetic defect unique from the abnormalities in previously described cases of primary renal glucosuria with different amino acid excretion patterns. Future investigations could determine whether the syndrome involves a defect in the SGLT2 gene.

Adult↗

PubMed1993

Alport-leiomyomatosis syndrome: an update.

Alport-leiomyomatosis syndrome is a polygenic syndrome with a dominant X-linked inheritance pattern resulting from a large deletion in the 5' end of the COL4A5 gene coding for the type IV collagen alpha 5 chains. Hypothetically, the deletion extends beyond the 5' end and probably includes a second contiguous gene responsible for leiomyomatosis (the DL gene) and even a third one coding for congenital cataract (the CCT gene).

Adolescent↗

PubMed2001

Anticipation, imprinting, trinucleotide repeat expansions and psychoses.

1. Since 1991, approximately 20 trinucleotide repeat expansion type neurodegenerative disorders have been reported. They are clinically characterized by anticipation, i.e., worsening severity or earlier age at onset with each succeeding generation for an inherited disease, and imprinting, i.e., a process whereby specific genes are differentially marked during parental gametogenesis, resulting in the differential expression of these genes in the embryo and adult. 2. The phenomenon of anticipation in psychoses has been pointed out since the 19th century; however, it was ignored because no one knew the genetic mechanism underlying this type of inheritance pattern at the time, and because of several possible biases. 3. The discovery of trinucleotide repeat expansion diseases has reawakened interest in the phenomenon of anticipation in psychiatric diseases. Anticipation has been confirmed in schizophrenia, mood disorders, and anxiety disorders in much more sophisticated manners, although still not perfectly. 4. Molecular approaches as well as clinical ones have been taken to reveal the involvement of trinucleotide repeat expansion mechanism in psychoses by means of direct analyses of candidate genes, RED and DIRECT. Most efforts have been made for CAG type trinucleotide repeats. So far, direct analyses have failed to reveal pathogenic gene(s). There were several positive RED data at first, however, nowadays there seems to be a tendency of much more negative results. The DIRECT results did not support trinucleotide repeat expansions mechanism in psychoses either. One plausable explanation for the 'false positive' result is the presence of CAG trinucleotide repeats which are highly polymorphic but not associated with an obvious abnormal phenotype. Screening for trinucleotide repeats other than ones of the CAG type remained to be performed.

Anticipation, Genetic↗

PubMed2001

Genetic basis of schizophrenia: trinucleotide repeats. An update.

1. Recent developments in technologies permit systematic screening of the entire human genome as a strategy for identification of susceptibility genes of small effect that influence risk to complex traits, like schizophrenia (Schz), inflammatory bowel disease, bipolar affective disorder (BPAD) etc. 2. Schizophrenia is known to have a high heritability and a complex inheritance pattern. Several studies provide evidence that both genes and environment play a role in the etiology of schizophrenia. Linkage studies have observed racial and sex bias in the genetic constitution of schizophrenia. Schizophrenia also manifests clinical anticipation and genomic imprinting. 3. "Dynamic mutations" or "tandem repeat expansions" in DNA, explain a number of observations associated with clinical anticipation and genomic imprinting. In patient populations, the repeat expands well beyond the normal range, altering the biological function of the gene. These sequence are unstable and increase in size between family members in successive generations, giving rise to greater severity of disease. 4. Several workers have reported an association of trinucleotide repeat length with adult- and child-onset schizophrenia. One such expanded allele has been found at the CTG18.1 locus on the 18th chromosome. Other genes known to have similar mutation are SEF2-1, which codes for a helix-loop-helix protein, hSKCa3 gene, which codes for a calcium-activated potassium channel and the transthyretin gene. In schizophrenic patients, significant difference in allele frequency distribution of these genes has been reported. 5. Population based genetic research would not only help identify different subgroups of this of schizophrenia.

Animals↗

PubMed1996

Functional and clinical consequences of mutations in the FSH receptor.

The follicle-stimulating hormone (FSH) is essential for normal gametogenesis. In females FSH is required for ovarian development and follicle maturation whereas in males FSH determines Sertoli cell number and quantitatively and qualitatively normal spermatogenesis. FSH action is mediated by a G-protein coupled receptor expressed solely in granulosa and Sertoli cells. The FSH-receptor (FSHR) gene is localized on chromosome 2 p21 and spans a region of 54 kb. It consists of ten exons; exon one to nine encode the large extracellular domain and the transmembrane domain is comprised of exon ten. Mutations in the FSHR gene could severely affect gametogenesis and result in infertility. Therefore screening programs have been initiated, in which patients with disturbed fertility were searched for mutations in the FSHR gene. Several Finnish families were identified displaying an inherited pattern of ovarian dysgenesis, a disease leading to streaky underdeveloped ovaries and primary amenorrhea. By genetic linkage the locus of the genetic defect was confined to chromosome 2 p21. Analysis of the FSHR gene resulted in the identification of a mutation (Ala189Val) homozygous in all affected females. Functional studies revealed that the mutation affects the proper protein folding and thereby inactivates the receptor. In a male patient hypophysectomized because of a pituitary tumor, who despite undetectable serum gonadotropins had normal semen parameters, we hypothesized an activating mutation of the FSHR. Screening of exon ten of the FSHR gene resulted in the identification of a Asp567Gly transition in the third intracytoplasmatic loop. Functional studies resulted in a 1.5-fold increase in basal cAMP production compared to wild type FSHR, indicating that the heterozygous mutation leads to a ligand-independent constitutive activation of the FSHR. This patient provides an exceptional model of nature defining the role of FSH in human spermatogenesis. Mutations of the FSHR might have differential effects in each gender. For example activating mutations have not been described in women, therefore it is not clear whether the constitutive activity of the receptor could disturb normal follicular development resulting in certain infertility.

Amino Acid Sequence↗

PubMed2004

Another case of cerebro-facio-thoracic dysplasia (Pascual-Castroviejo syndrome).

We report another case of cerebro-facio-thoracic dysplasia (Pascual-Castroviejo syndrome) characterized by mental retardation and characteristic facies: narrow forehead, synophris, hypertelorism, broad nasal bridge, long philtrum, micrognathia, triangular-shaped mouth and low posterior hairline, and also brachycephaly, calcified clinoid ligaments, and upper rib deformities. Although the severity of mental retardation within the syndrome varies, the reported case shows not only a severe degree, but also cerebral malformations not reported in any of the previous cases of cerebro-facio-thoracic syndrome. These include cortical-subcortical atrophy with hypoplasia of the corpus callosum, and of the cerebellar vermis. We also discuss the inheritance pattern and differential diagnosis, comparing this phenotype to other similar dysmorphic syndromes.

Adult↗

PubMed2002

Neurocutaneous disorders.

"Neurocutaneous disorders" is a catch-all phrase that includes all disorders involving both the nervous systems and the skin. These may range from disorders in which cutaneous findings are essential to diagnosis to those with less significant involvement of the skin. Because of the variety of disorders that involve the skin and the nervous system, this article reviews a few of the more essential diagnoses, and those with recent advancements in diagnosis and management. Many of these diseases are single gene disorders, for which the genes have been discovered in the past few years. The article is divided into sections, highlighting disorders transmitted by different inheritance pattern.

Ataxia Telangiectasia↗

PubMed2003

Atp10a, the mouse ortholog of the human imprinted ATP10A gene, escapes genomic imprinting.

The mouse Atp10a gene is located at the border of an imprinted domain distal to the p-locus on mouse chromosome 7. The localization of Atp10a neighboring the maternally expressed gene Ube3a in the imprinted domain and an unusual inheritance pattern of the obesity phenotype with a p-locus deletion have suggested that Atp10a might be imprinted and associated with body fat. Recently, its human ortholog, ATP10A, was identified as the second imprinted gene with maternal expression in the human chromosome 15q11-q13 imprinted domain. To elucidate the imprinting status of Atp10a, we performed expression analysis in various tissues from reciprocal crosses between C57BL/6 and PWK (divergent strains of Mus musculus) mice. The results revealed that Atp10a was biallelically expressed in all tissues examined. Furthermore, there was no differential methylation in the CpG island and no antisense transcripts of the gene. These findings suggest that the mouse Atp10a gene escapes genomic imprinting.

Adenosine Triphosphatases↗

PubMed2000

Genetics of systemic lupus erythematosus. Clinical implications.

Rheumatic diseases have long been recognized as having complex inheritance patterns. It has recently been estimated that over 100 genes may be implicated in the SLE disease process. Identification of these genes has led to a greater understanding of the etiopathogenesis of SLE and is beginning to lead to new types of interventions directed at correcting aberrant biological processes.

Animals↗

PubMed2002

Mechanisms of disease: Fuchs' endothelial dystrophy.

Fuchs' endothelial dystrophy is a common disease that has been widely studied since its initial report in 1910 by Ernst Fuchs. Although its clinical course and pathologic characteristics are well described, the etiology and inheritance pattern are still ambiguous. Ongoing work is evaluating the role of mitochondrial DNA in the pathogenesis of FED. Significant advances in the surgical treatment of FED, in part utilizing some of the techniques of refractive surgery, are promising thus far. Larger case series are needed to fully assess the safety, efficacy and indications of these techniques. Indeed, the time is right to take "a fresh look at an aging disease" [9].

Diagnosis, Differential↗

PubMed2003

Genetics of uveitis.

Uveitis phenotypes can differ substantially, and most uveitis diseases are considered polygenic with complex inheritance patterns. When considering the genetics of these diseases, common threads can be identified. For example, in virtually every polygenic disease studied, there exists an HLA genetic association. This association can be strong, such as the associations of HLA-B27 with AAU and HLA-A29 with BSCR; or it can be more subtle, involving several HLA genes or a combination of HLA genes that compose specific haplotypes. In many of these conditions, it is hypothesized that genes other than classic MHC genes but located at the MHC locus may be important susceptibility genes. Genome-wide scans and other genetic methods are becoming increasingly successful in identifying genetic loci and candidate genes in many inflammatory disorders that have an uveitic component. It will be important to test these findings as uveitis-specific genetic factors. Therefore, the burgeoning understanding of the human genome promises to result in new insight into the pathogenesis of uveitis.

Humans↗

PubMed2006

Deficiency of the seventh component of complement in a Taiwanese boy.

Inherited complement deficiencies are rare, particularly those associated with late components of the complement cascade. We report a 5-year-4-month-old Taiwanese boy with systemic meningococcal infection who had undetectable CH50 level of < 6 U/mL (normal, 32.6-39.8 U/mL). Levels of C3, C4, C5, C6 and C8 were normal, but C7 was undetectable (< 5.8 mg/dL; reference, 55-85 mg/dL). The patient's sister was also C7-deficient (CH50 < 6 U/mL, C7 < 5.8 mg/dL). His father's CH50 was 25.9 U/mL and C7 was 27.8 mg/dL. His mother's CH50 was 31.2 U/mL and C7 was 22.7 mg/dL. His parents thus both had a partial complement deficiency, indicating an autosomal codominant inheritance pattern. Awareness of the possibility of late complement deficiency is important as they comprise a small percentage of patients who present with disseminated meningococcal disease or other serious infections caused by encapsulated organisms.

Anti-Bacterial Agents↗

PubMed1988

Population genetics and molecular biology of the childhood chronic arthropathies.

Recent immunogenetic studies of JRA patients have both helped to clarify subdivision into distinctive subtypes and identified those subtypes which may be related to adult rheumatic disease. Despite the variability of HLA associations from different geographic sources, a consensus appears to be emerging as to the most important associations. In addition to the HLA-DR locus, distinct associations with the HLA-DP and HLA-DQ loci have been described. Family studies have suggested an increased risk with certain haplotypes, particularly in the EOPA JRA population. Although inheritance patterns remain to be defined, recent studies with monoclonal antibodies, alloreactive T cell clones, and DNA have identified the existence of specific epitopes encoded by a variety of Ia molecules which may be more directly related to disease susceptibility. The concept of an epitope dose effect is put forward to account for the variable HLA association with disease, particularly with regard to EOPA JRA. Further developments in the definition of micropolymorphisms of Ia molecules at the genomic level as well as the possible involvement of other genetic loci, in particular T cell receptor variable gene products, should help clarify our understanding of the role of genetic factors in the aetiology of JRA. The studies of the last two decades indicate that inferences made by Carter (1969) on the 'polygenic, weakly penetrant genetic effect' in autoimmune disease are indeed applicable to JRA.

Arthritis, Juvenile↗

PubMed2001

Nebulin expression in patients with nemaline myopathy.

Nemaline myopathy is a structural congenital myopathy which may show both autosomal dominant and autosomal recessive inheritance patterns. Mutations in three different genes have been identified as the cause of nemaline myopathy: the gene for slow alpha-tropomyosin 3 (TPM3) at 1q22-23, the nebulin gene (NEB) at 2q21.1-q22, and the actin gene (ACTA1) at 1q42. The typical autosomal recessive form appears to be the most common one and is caused by mutations in the nebulin gene. We have studied the pattern of nebulin labeling, in patients with the typical congenital form (ten patients), the severe congenital form (two patients) or the mild, childhood-onset form (one patient), using antibodies against three different domains of nebulin. A qualitative and quantitative nebulin analysis in muscle tissue showed the presence of nebulin in myofibers from all patients. Some differences relating to the rod structure were observed. The majority of the largest subsarcolemmal rods were not labeled with the N2 nebulin antibody (I-band epitope) and showed an indistinct pattern with the two antibodies directed to the Z-band portion of nebulin (epitopes M176-181 and serine-rich domain). Diffuse rods were not revealed using the three antibodies. A discordant pattern of nebulin N2 epitope labeling was found in two affected sisters with a mutation in the nebulin gene, suggesting that modifications in nebulin distribution inside the rods might occur with the progression of the disease. Western blot analysis showed no direct correlation with immunofluorescence data. In nine patients, the band had a molecular weight comparable to the normal control, while in one patient, it was detected with a higher molecular weight. Our results suggest that presence/absence of specific nebulin Z-band epitopes in rod structures is variable and could depend on the degree of rod organization.

Adolescent↗

PubMed1998

Genetic aspects of Hirschsprung's disease.

Hirschsprung's disease (HD) is a relatively common cause of intestinal obstruction in the newborn, characterized by the absence of autonomic ganglion cells in the terminal bowel. Existence of familial cases indicates that genetic factors may be involved in the etiology of some cases of HD. Different inheritance patterns observed in subsets of HD families or kindreds, and the detection of different chromosome aberrations in some HD patients, suggest genetic heterogeneity of HD. Recent expansion of molecular genetics has identified multiple susceptibility genes of HD. These include the RET gene, the glial cell-derived neurotrophic factor gene, the endothelin-B receptor gene, and endothelin-3 gene. Furthermore, some other genes or genetic factors are speculated to be implicated in the development of HD, and it is believed that multiple factors play a role in disease development in some cases. Taken together, these data suggest and may explain the complexity of the etiology of HD. This review focuses on recent advances in our understanding of the genetic aspects of HD.

Drosophila Proteins↗

PubMed1998

Factor V Leiden mutation: a nursing perspective.

The factor V Leiden mutation is a recently described autosomal dominant genetic risk factor for venous thromboembolism (VTE). Persons who are heterozygous or homozygous for this disorder are at 4 to 7 times and 50 to 100 times increased risk, respectively, for VTE. In particular, women have unique challenges because the presence of the Leiden mutation in combination with pregnancy or use of oral contraceptives results in an even greater increased risk for VTE. This article will review the factor V Leiden mutation, its association with VTE, and the genetic inheritance pattern and ethnic distribution. Oral contraceptive use, pregnancy, and hormone replacement therapy in women with the Leiden mutation will be discussed. Screening issues and management for all patients, and women in particular, will be addressed. Nursing implications for care management of this group of patients is complex and requires evaluation of the significance of newly defined genetic disorders such as the factor V Leiden mutation. Nurses need to be knowledgeable about genetic screening, risk factors, risk-reduction counseling, and considerations for long-term therapy, which include quality of life issues. Two case studies exemplify many of the issues that will be discussed.

Adult↗