Bipolar affective disorders linked to DNA markers on chromosome 11

An analysis of the segregation of restriction fragment length polymorphisms in an Old Order Amish pedigree has made it possible to localize a dominant gene conferring a strong predisposition to manic depressive disease to the tip of the short arm of chromosome 11.     

No linkage of chromosome 5q11-q13 markers to schizophrenia in Scottish families

Recent work suggests that an autosomal dominant gene for schizophrenia may be located on the 5q11-q13 region of chromosome 5 (refs 1 and 2): a report of schizophrenia associated with trisomy 5q11-q13 in two members of a family of Chinese origin prompted the discovery of linkage with markers p105-599Ha and p105-153Ra in five Icelandic and two English schizophrenic families. The strongest linkage was observed when the phenotype was broadly defined to include minor psychiatric diagnoses not traditionally considered part of the schizophrenia spectrum. By contrast, no evidence was found of linkage in a single multiplex Swedish schizophrenic pedigree. To determine whether these conflicting results arise from genetic and/or uncertainties in defining the schizophrenic phenotype, we examined fifteen Scottish schizophrenic families with restriction fragment length polymorphisms that span this region. We found no evidence for linkage, regardless of how broadly or narrowly the schizophrenic phenotype is defined, and conclude that a susceptibility locus, whose presence awaits confirmation, on the proximal portion of the long arm of chromosome 5 can be responsible for only a minority of cases of familial schizophrenia.     

Clinical and genetic analysis of two Chinese families with benign familial neonatal convulsions

Benignfamilialneonatalconvulsions(BFNC)is arareautosomaldominantinheritedepilepsysyn dromecharacterizedbyunprovokedpartialorgeneral izedseizures.Theseizuresusuallyoccurfromthesec onddayofbirthtothesixthmonthandremitsponta neouslyafterseveralweekstomonths.Mostindivid ualsareseizure freebytheageofsixmonths.The serumchemistryandneuroradiologicalexaminations,interictalelectroencephalogram(EEG),andpsy chomotordevelopmentareusuallynormal.However,10%to15%ofpatientshavetheriskofseizurere currencela…     

Clinical and genetic analysis of two Chinese families with benign familial neonatal convulsions

Benign familial neonatal convulsions (BFNC) is a rare autosomal dominant inherited epilepsy syndrome. Two voltage-gated potassium channel genes, KCNQ2 and KCNQ3, have been identified as the genes responsible for BFNC. Here we report two Chinese families with clinical histories of typical BFNC. Using six microsatellite markers, two located at KCNQ2 locus and four at KCNQ3 locus, linkage analysis was performed in the two families, which excluded the linkage of BFNC to KCNQ3, but could not exclude the linkage to KCNQ2. Direct DNA sequencing of the KCNQ2 gene in the two families was performed, and two formerly unknown polymorphisms were identified, but no KCNQ2 mutation was found in the two families. Our study suggests the genetic heterogeneity in Chinese families with BFNC and proves the existence of a new gene locus for BFNC.     

Ryanodine receptor gene is a candidate for predisposition to malignant hyperthermia

Malignant hyperthermia (MH) is a potentially lethal condition in which sustained muscle contracture, with attendant hypercatabolic reactions and elevation in body temperature, are triggered by commonly used inhalational anaesthetics and skeletal muscle relaxants. In humans, the trait is usually inherited in an autosomal dominant fashion, but in halothane-sensitive pigs with a similar phenotype, inheritance of the disease is autosomal recessive or co-dominant. A simple and accurate non-invasive test for the gene is not available and predisposition to the disease is currently determined through a halothane- and/or caffeine-induced contracture test on a skeletal muscle biopsy. Because Ca2+ is the chief regulator of muscle contraction and metabolism, the primary defect in MH is believed to lie in Ca2+ regulation. Indeed, several studies indicate a defect in the Ca2+ release channel of the sarcoplasmic reticulum, making it a prime candidate for the altered gene product in predisposed individuals. We have recently cloned complementary DNA and genomic DNA encoding the human ryanodine receptor (the Ca2(+)-release channel of the sarcoplasmic reticulum) and mapped the ryanodine receptor gene (RYR) to region q13.1 of human chromosome 19 (ref. 14), in close proximity to genetic markers that have been shown to map near the MH susceptibility locus in humans and the halothane-sensitive gene in pigs. As a more definitive test of whether the RYR gene is a candidate gene for the human MH phenotype, we have carried out a linkage study with MH families to determine whether the MH phenotype segregates with chromosome 19q markers, including markers in the RYR gene. Co-segregation of MH with RYR markers, resulting in a lod score of 4.20 at a linkage distance of zero centimorgans, indicates that MH is likely to be caused by mutations in the RYR gene.     

Close linkage of glucokinase locus on chromosome 7p to early-onset non-insulin-dependent diabetes mellitus.

Non-insulin-dependent diabetes mellitus (NIDDM) is a major health problem, affecting 5% of the world population. Genetic factors are important in NIDDM, but the mechanisms leading to glucose intolerance are unknown. Genetic linkage has been investigated in multigeneration families to localize, and ultimately identify, the gene(s) predisposing to NIDDM. Here we report linkage between the glucokinase locus on chromosome 7p and diabetes in 16 French families with maturity-onset diabetes of the young, a form of NIDDM characterized by monogenic autosomal dominant transmission and early age of onset. Statistical evidence of genetic heterogeneity was significant, with an estimated 45-95% of the 16 families showing linkage to glucokinase. Because glucokinase is a key enzyme of blood glucose homeostasis, these results are evidence that a gene involved in glucose metabolism could be implicated in the pathogenesis of NIDDM.     

Close genetic linkage between X-linked retinitis pigmentosa and a restriction fragment length polymorphism identified by recombinant DNA probe L1.28

Retinitis pigmentosa (RP) is a group of retinal degeneration characterized by progressive visual field loss, night blindness and pigmentary retinopathy. Its prevalence is in the region of 1-2 in 5,000 of the general population, making it one of the commoner causes of blindness in early and middle life. Although 36-48% of RP patients are isolated cases, the remainder show autosomal dominant, autosomal recessive or X-linked modes of inheritance. The X-linked variety ( XLRP ) is found in 14-22% of RP families in the UK. In the present study, X chromosome-specific recombinant DNA probes which can detect restriction fragment length polymorphisms have been used to localize the XLRP gene(s) to a subregion of the X chromosome using linkage analysis. One of the probes, L1.28, has been shown to be closely linked to XLRP in five kindreds, with 95% confidence limits of 0-15 centimorgans (maximum LOD score of 7.89 at a distance of 3 centimorgans). This suggests that the XLRP locus lies on the proximal part of the short arm of the X chromosome. This probe is potentially useful for carrier detection and early diagnosis in about 40% of cases, provided that genetic heterogeneity can be excluded by analysis of further families.     

Exclusive gene mapping of congenital microphthalmia in a Chinese family

Congenital microphthalmia is a developmental ocular disorder and might be caused by the mutations in the genes involved in eye development. To uncover the genetic cause in a six-generation Chinese pedigree with autosomal dominant congenital microphthalmia, we performed genescan and linkage analysis in this family. Fourteen microsatellite markers on chromosomes 3, 11, 14 and 15 were selected as genetic markers according to the five pre-viously reported loci associated with microphthalmia (MITF, SOX2, PAX6, MCOP and NNO2). The genomic DNA of each member in the pedigree was amplified with 14 pairs of fluorescence labeled primers. Genome screening and genotyping were conducted on ABI377 DNA sequencer and linkage analysis was performed with Linkage software package. All two-point LOD scores of linkage analysis between the suggested disease genes and microsatellite markers were <-2, which indicated that none of the five genes were responsible for microphthalmia in this Chinese family. Microphthalmia in this family may be caused by mutation in a new gene which is essential in eye development.     

Close linkage of c-Harvey-ras-1 and the insulin gene to affective disorder is ruled out in three North American pedigrees

Affective disorder (AD) is one of the major forms of functional psychoses. Although the mode of transmission is uncertain, family, twin and adoption studies strongly suggest a genetic involvement. Because a basic biochemical abnormality is not known, direct analysis of the disease using a probe for the defective gene is not possible. However, a specific locus can be tested for its relevance to the aetiology of AD by genetic linkage, using restriction fragment length polymorphisms (RFLPs). Using probes for the c-Ha-ras-1 oncogene and the insulin gene, Gerhard et al. and Egeland et al. found convincing evidence for close linkage between these markers and a locus for AD in a large Old Order Amish pedigree. In an attempt to confirm this finding, we examined three bipolar pedigrees outside the Amish population. Our results indicate the absence of linkage from 0 to 15% recombination frequency between AD and the insulin gene-HRAS1 region in these pedigrees.     

肢带型肌营养不良一家系致病基因排除性定位

为了定位一个常染色体显性遗传肢带型肌营养不良家系的致病基因（ADLGMD）,采用13个荧光微卫星标记对收集到的一个包括4代33人的ADLGMD家系进行连锁分析,所选择的标记覆盖了3个已知ADL—GMD致病基因位点和4个已报道的致病基因定位区段．通过Linkage 5．1软件包计算连锁概率,各位点连锁分析所得的LOD值均小于-3,显示该家系致病基因与这7个位点均不连锁．该家系的肌营养不良症致病基因不在已知的位点内,很可能是一个新致病基因．     

Genetic linkage between X-chromosome markers and bipolar affective illness

A pedigree study shows close linkage of bipolar affective illness (manic depression) to the X-chromosome markers colour blindness and glucose-6-phosphate dehydrogenase deficiency. The maximum lod score ranges from 7.52 (assuming homogeneity) to 9.17 (assuming heterogeneity); that is, the odds in favour of linkage range between 3 X 10(7) to 1 and 10(9) to 1. These results provide confirmation that a major psychiatric disorder can be caused by a single genetic defect. As a possible first step in characterizing the primary genetic abnormality, this finding may have important implications for the aetiology, nosology, pathophysiology and, possibly, prevention and treatment of bipolar affective disorder. It also provides a means for identifying and characterizing homogeneous populations of patients and may help in clarifying aetiological heterogeneity.     

Mutations in the human retinal degeneration slow gene in autosomal dominant retinitis pigmentosa.

The murine retinal degeneration slow (rds) gene is a semidominant mutation with a phenotype having rod and cone photoreceptors that develop abnormally and then slowly degenerate. The phenotype is a possible model for retinitis pigmentosa, one of the scores of hereditary human retinal degenerations, which is also characterized by photoreceptor degeneration. We report here three mutations of the human homologue of the rds gene (RDS) that cosegregate with autosomal dominant retinitis pigmentosa in separate families. Our results indicate that some cases of autosomal dominant retinitis pigmentosa are due to mutations at the RDS locus.     

The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenita

Dyskeratosis congenita is a progressive bone-marrow failure syndrome that is characterized by abnormal skin pigmentation, leukoplakia and nail dystrophy. X-linked, autosomal recessive and autosomal dominant inheritance have been found in different pedigrees. The X-linked form of the disease is due to mutations in the gene DKC1 in band 2, sub-band 8 of the long arm of the X chromosome (ref. 3). The affected protein, dyskerin, is a nucleolar protein that is found associated with the H/ACA class of small nucleolar RNAs and is involved in pseudo-uridylation of specific residues of ribosomal RNA. Dyskerin is also associated with telomerase RNA (hTR), which contains a H/ACA consensus sequence. Here we map the gene responsible for dyskeratosis congenita in a large pedigree with autosomal dominant inheritance. Affected members of this family have an 821-base-pair deletion on chromosome 3q that removes the 3' 74 bases of hTR. Mutations in hTR were found in two other families with autosomal dominant dyskeratosis congenita.     

A Met-to-Val mutation in the skeletal muscle Na+ channel alpha-subunit in hyperkalaemic periodic paralysis.

HYPERKALAEMIC periodic paralysis (HYPP) is an autosomal dominant disease that results in episodic electrical inexcitability and paralysis of skeletal muscle. Electrophysiological data indicate that tetrodotoxin-sensitive sodium channels from muscle cells of HYPP-affected individuals show abnormal inactivation. Genetic analysis of nine HYPP families has shown tight linkage between the adult skeletal muscle sodium channel alpha-subunit gene on chromosome 17q and the disease (lod score, z = 24; recombination frequency 0 = 0), strongly suggesting that mutations of the alpha-subunit gene cause HYPP. We sequenced the alpha-subunit coding region isolated from muscle biopsies from affected (familial HYPP) and control individuals by cross-species polymerase chain reaction-mediated complementary DNA cloning. We have identified an A----G substitution in the patient's messenger RNA that causes a Met----Val change in a highly conserved region of the alpha-subunit, predicted to be in a transmembrane domain. This same change was found in a sporadic case of HYPP as a new mutation. We have therefore discovered a voltage-gated channel mutation responsible for a human genetic disease.     

Gene for chronic proximal spinal muscular atrophies maps to chromosome 5q

Proximal spinal muscular atrophies represent the second most common fatal, autosomal recessive disorder after cystic fibrosis. The childhood form is classically subdivided into three groups: acute Werdnig-Hoffmann (type I), intermediate Werdnig-Hoffmann disease (type II) and Kugelberg-Welander disease (type III). These different clinical forms have previously been attributed to either genetic heterogeneity or variable expression of different mutations at the same locus. Research has been hindered because the underlying biochemical defect is unknown, and there are insufficient large pedigrees with the most common and severe form (type I) available for study. Therefore, we have undertaken a genetic linkage analysis of the chronic forms of the disease (types II and III) as an initial step towards the ultimate goal of characterizing the gene(s) responsible for all three types. We report here the assignment of the locus for the chronic forms to the long arm of chromosome 5 (5q12-q14), with the anonymous DNA marker D5S39, in 24 multiplex families of distinct ethnic origin. Furthermore, no evidence for genetic heterogeneity was found for types II and III in our study, suggesting that these two forms are allelic disorders.     

Re-evaluation of the linkage relationship between chromosome 11p loci and the gene for bipolar affective disorder in the Old Order Amish

Reanalysis of an Old Order Amish pedigree, to include several new individuals and two changes in clinical status, markedly reduces the probability of linkage between bipolar affective disorder and the Harvey-ras-1 oncogene and insulin loci on chromosome 11. This linkage can be excluded using a large lateral extension of the original Amish pedigree.     

GLI3 zinc-finger gene interrupted by translocations in Greig syndrome families.

The Greig cephalopolysyndactyly syndrome (GCPS) is an autosomal dominant disorder affecting limb and craniofacial development in humans. GCPS-affected individuals are characterized by postaxial polysyndactyly of hands, preaxial polysyndactyly of feet, macroephaly, a broad base of the nose with mild hypertelorism and a prominent forehead. The genetic locus has been pinpointed to chromosome 7p13 by three balanced translocations associated with GCPS in different families. This assignment is corroborated by the detection of two sporadic GCPS cases carrying overlapping deletions in 7p13 (ref. 7), as well as by tight linkage of GCPS to the epidermal growth factor receptor gene in 7p12-13 (ref. 8). Of the genes that map to this region, those encoding T cell receptor-gamma, interferon-beta 2, epidermal growth factor receptor, and Hox1.4, a potential candidate gene for GCPS, have been excluded from the region in which the deletions overlap. Here we show that two of the three translocations interup the GLI3 gene, a zinc-finger gene of the GLI-Krüppel family already localized to 7p13 (refs 5, 6). The breakpoints are within the first third of the coding sequence. In the third translocation, chromosome 7 is broken at about 10 kilobases downstream of the 3' end of GLI3. Our results indicate that mutations disturbing normal GLI3 expression may have a causative role in GCPS.     

Genetic linkage studies suggest that Alzheimer's disease is not a single homogeneous disorder. FAD Collaborative Study Group

Alzheimer's disease, a fatal neurodegenerative disorder of unknown aetiology, is usually considered to be a single disorder because of the general uniformity of the disease phenotype. Two recent genetic linkage studies revealed co-segregation of familial Alzheimer disease with the D21S1/S11 and D21S16 loci on chromosome 21. But two other studies, one of predominantly multiplex kindreds with a late age-of-onset, the other of a cadre of kindreds with a unique Volga German ethnic origin, found absence of linkage at least to D21S1/S11. So far it has not been possible to discern whether these conflicting reports reflect aetiological heterogeneity, differences in methods of pedigree selection, effects of confounding variables in the analysis (for example, diagnostic errors, assortative matings), or true non-replication. To resolve this issue, we have now examined the inheritance of five polymorphic DNA markers from the proximal long arm of chromosome 21 in a large unselected series of pedigrees with familial Alzheimer's disease. Our data suggest that Alzheimer's disease is not a single entity, but rather results from genetic defects on chromosome 21 and from other genetic or nongenetic factors.     

Assignment of multiple endocrine neoplasia type 2A to chromosome 10 by linkage

Multiple endocrine neoplasis type 2A (MEN2A) is one of several kinds of cancers that appear to be inherited in an autosomally dominant fashion. We have assigned the MEN2A locus to chromosome 10 by linkage with a new DNA marker (D10S5). The linkage led us to investigate other chromosome 10 markers and demonstrate linkage between the disease locus and the interstitial retinol-binding protein (IRBP) gene. The D10S5 locus was sublocalized to 10q21.1 by hybridization in situ and the IRBP gene to p11.2----q11.2 with a secondary site at q24----q25. The linkages were established using 292 members of five families, three different restriction fragment length polymorphisms (RFLPs) at D10S5 and two RFLPs recognized by the IRBP probe. The recombination frequencies from pairwise linkage analysis between the disease and two marker loci D10S5 and IRBP were 0.19 and 0.11, with maximum lod scores of 3.6 and 8.0 respectively. Ordering of the three loci by multipoint analysis placed the IRBP gene approximately midway between the disease and D10S5 loci.