Inheritance of ocular dominance

Evidence for an inherited component in the determination of the preferred eye in sighting dominance is presented that replicates the earlier findings by Merrell (1957). Significantly more left-sighting-preferent individuals were found in the progeny of R×L and L×L matings than in the R×R matings.The preparation of this study was supported by National Institute of Mental Health Grant MH-21989.     

The homeotic genespineless-aristapedia affects geotaxis inDrosophila melanogaster

The homeotic mutationspineless-aristapedia (ss ^a ) transforms the aristae into second tarsi. Flies with aSS ^a phenotype also show extremely positive geotaxis as measured in a Hirsch-type geotaxis maze. Other antennal mutants and flies with their aristae amputated do not show such extreme positive geotaxis. Deletion analysis has comapped the geotaxis effect withSS ^a in band 89C on the third chromosome. Finally, a biometrical analysis has detected additional genes on the X chromosome that also affects geotaxis.This work was supported by a Charles and Johanna Busch Memorial Award to T.R.M. and an Anne B. and James H. Leathem Scholarship Fund Award to P.A.M.Department of Biological Sciences and Bureau of Biological Research, Nelson Biological Laboratories     

Tumor necrosis factor receptor II (TNFRII) exon 6 polymorphism in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a complex autoimmune disease that exhibits extensive clinical heterogeneity. Several studies have suggested a role for tumor necrosis factor alpha (TNFalpha) in SLE and recently, the locus encompassing the TNF receptor II (TNFRII), which is a mediator of TNF effect, was amongst the candidate loci suggested by genetic linkage studies of multi-case SLE families. Komata et al. reported an association between a polymorphism at position 196 (R allele) of TNFR II and SLE in Japanese patients. We have typed SLE patients from two different ethnic populations, Spanish and UK Caucasoids, for this polymorphism using a polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP)-based technique. No significant differences in allele or genotype frequencies were found between cases and matched controls in either population. The TNFRII 196R allele does not appear to be associated with SLE susceptibility in either Spanish or UK populations.     

Association study of a SNAP‐25 microsatellite and attention deficit hyperactivity disorder

Several lines of evidence implicate synaptosomal‐associated protein of 25 kDa (SNAP‐25) in the etiology of attention deficit hyperactivity disorder (ADHD). Most notably, the coloboma mouse mutant, considered to be a good animal model of hyperactivity, has a deletion spanning this gene. Introducing a SNAP‐25 transgene into these animals alleviates hyperlocomotion. We have identified a novel microsatellite repeat in SNAP‐25 located between the 5′UTR and the first coding exon, and tested for association with ADHD. Case‐control analyses suggest there may be a role of this polymorphism in ADHD, with one allele over‐represented in controls and another over‐represented in probands. Within‐family tests of linkage and association confirmed these findings. Further work is needed to ascertain the role of SNAP‐25 in ADHD and assess the functional significance of this polymorphism. © 2002 Wiley‐Liss, Inc.     

Aetiology of congenital absence of vas deferens: genetic study of three generations

Bilateral congenital absence of the vas deferens (CAVD) is aform of male sterility (found in otherwise normal men) of unknownaetiology. Because males with cystic fibrosis (CF) almost invariablyhave CAVD as well, we investigated the hypothesis that men withisolated CAVD might share a common genetic background with maleswith CF. Genetic testing for CF was carried out in three generationsof subjects: 44 patients with CAVD and their wives, 24 of theirparents, and 13 of their offspring generated by microsurgicalepididymal sperm aspiration (MESA) and in-vitro fertilization(IVF). DNA extracted from peripheral lymphocytes was amplifiedby the polymerase chain reaction (PCR) and then analysed for12 mutations in the cystic fibrosis transmembrane conductanceregulatory (CFTR) gene. Among 44 patients tested with CAVD,26 (59%) were positive for at least one CF mutation, while thecarrier frequency for CF mutations in the general populationis only 4%. Four patients were found to be compound heterozygotes,three with genotypes Delta F-508/R117H, one with R553X/R117H.Among 24 parents tested, 15 (seven fathers, eight mothers) hadsons with CAVD who were positive for CF mutations. Of these,nine (four fathers and five mothers) were found to be carriersfor CF mutations. These four fathers, although carriers of CFmutations, were obviously fertile. Of the 13 offspring tested,six (three boys and three girls) had CF positive fathers. Ofthese, three (two girls and one boy) were found to be carriersfor CF mutations. These MESA/IVF children are the first offpsringto whom men with CAVD have been able to transmit CF mutations.All of the MESA/IVF male offspring (like their grandfathers)had a normal vas deferens bilaterally, including one carrierfor Delta F-508. This study revealed, by genetic testing ofotherwise normal men with sterility caused by CAVD, a new populationof patients with a variant form of CF and highlighted the possibilitythat carrier frequency for CF is higher than previously thought.Compound heterozygosity for CF mutations and not carrier conditionis associated with isolated CAVD. It is concluded that geneticcounselling and screening for CF should be offered to couplesundergoing sperm aspiration and IVF procedures when CAVD isa factor in their infertility.     

Iα1基因hs1,2 区B等位基因与IgA肾病的易感性相关

［摘要］ 目的：研究Iα1 hs1,2 VNTR多态性与我国IgA肾病的相关关系。 方法： 采集419例肾活检证实的IgA肾病患者及其一级亲属、条件相当的201例健康志愿者血样，提取基因组DNA。用PCR产物直接电泳法鉴定Iα1 hs1,2 VNTR基因型，采用以家庭为基础的传递/不平衡分析（TDT）和单倍型相对危险度（HRR），以及病例-对照研究分析Iα1 hs1,2 VNTR多态性与我国IgA肾病的相关关系。 结果： ① TDT分析结果显示Iα1 hs1,2 VNTR B等位基因从杂合子父母向患者传递的频率显著高于预期值(101 Trios, χ2=6.818, P＜0.01，扩展TDT分析也得到相同结果(164家庭, χ2=7.583, P＜0.01)。②与TDT结果一致，HRR分析同样显示Iα1 hs1,2 VNTR B等位基因的过度传递 (P＜0.05, χ2=4.122, HRR=1.180)， 而BB基因型具有更强的患病倾向 (P＜0.05, χ2=4.411, OR=1.538)。③病例-对照研究显示IgA肾病组B 等位基因频率显著高于正常对照组(χ2=6.968, P＜0.05)。 结论： Iα1 hs1,2 VNTR基因多态性与我国IgA肾病患者的易感性相关。     

Molecular analysis of C3 allotypes in patients with nephritic factor.

The autoantibody nephritic factor (NeF) leads to complement consumption in vivo and is associated with type II mesangiocapillary glomerulonephritis (MCGN II) and partial lipodystrophy (PLD). The third component of complement (C3) exists in two common allotypic forms, C3S and C3F, distinguished at the protein level by electrophoresis. An increased frequency of the rarer C3F allele has been reported in several autoimmune conditions, including one small series of patients with NeF. However, patients with NeF have low levels of circulating C3 so that allotyping at the protein level is difficult. The molecular basis of the S/F polymorphism has recently been established: a single base change at the DNA level encodes a single amino acid substitution at the protein level. A second polymorphism, closely linked to the first, is defined by the MoAb HAV 4-1, and is also due to a single base change. These polymorphisms can therefore be analysed at the DNA level. We have used the amplification refractory mutation system (ARMS), a modification of the polymerase chain reaction (PCR), to analyse these two C3 polymorphisms at the DNA level in 26 patients with NeF. The allele frequencies of C3S and C3F were 0.673 and 0.327 (predicted values 0.79 and 0.2, chi 2 = 4.813, P < 0.05), giving a relative risk of 2.1 for the development of NeF conferred by the presence of a C3F allele. The HAV 4-1 allele frequencies were (-) 0.71 and (+) 0.29, i.e. not significantly different than predicted from the linked C3S/F allele frequencies. This is the largest series of patients with NeF yet published, and our data confirm an association between C3F and NeF. Possible mechanisms for for this link are discussed.     

Correlates of genetic risk for non-syndromic cleft lip with or without cleft palate

Mitchell LE, Risch N. Correlates of genetic risk for non-syndromic cleft lip with or without cleft palate. Clin Genet 1993: 43: 255–260. © Munksgaard, 1993 Multivariate analysis was used to determine which characteristics: sex of the proband, sibling sex, severity of the proband's defect or family history, are the best predictors of recurrence risk among siblings of individuals with non-syndromic cleft lip with or without cleft palate (CL \pm P). Sibling recurrence risks are not significantly related to the sex of the proband. Severity of the proband's defect, classified by the extent of the lip defect (unilateral versus bilateral), was found to be a significant predictor of sibling recurrence, whereas involvement of the palate in the proband's defect was not. A positive family history of clefting (i.e. at least one affected first-degree relative in addition to the proband) and the sex of the sibling were also found to be significant predictors of sibling recurrence. The associations between sibling risk and family history, and sibling risk and bilaterality of the proband's defect appear to be mildly confounded. After adjusting for the effects of family history, the risk to siblings of probands with bilateral lip defects is twice the risk to siblings of probands with unilateral defects (O.R. = 2.00; 95% C.I. 1.25-3.19). A positive family history of clefting increases the risk to siblings by greater than 4-fold (O.R. =4.49; 95% C.I. 2.74-7.35), after adjusting for the extent of the proband's lip defect. These results provide a rational strategy for identifying subsets of the ‘at risk’ population which have markedly different recurrence risks. This information is important for genetic counseling, since it allows for more precise estimation of sibling recurrence risks in individual cases. Furthermore, our findings indicate that the power to detect linkage between a genetic marker or a candidate gene and CL \pm P will increase if the study population is ascertained through individuals with bilcteral clefts of the lip, rather than through individuals with either unilateral or bilateral CL \pm P.     

Genetic dissection of the complex pathological manifestations of collagen disease in MRL/lpr mice

An MRL strain of mice bearing a Fas-deletion mutant gene, lpr, MRL/MpJ-lpr/lpr (MRL/lpr) develops collagen disease involving vasculitis, glomerulonephritis, arthritis and sialoadenitis, each of which has been studied as a model for polyarteritis, lupus nephritis, rheumatoid arthritis and Sjögren’s syndrome, respectively. Development of such lesions seems dependent on host genetic background since the congenic C3H/HeJ-lpr/lpr (C3H/lpr) mice rarely develop them. To identify the gene loci affecting each lesion, a genetic dissection of these complex pathological manifestations was carried out. First, histopathological features in MRL/lpr, C3H/lpr, (MRL/lpr × C3H/lpr) F1 intercross, and MRL/lpr × (MRL/lpr × C3H/lpr) F1 backcross mice were analyzed. Genomic DNA of the backcross mice were subjected to association studies by Chi-squared analysis for determining which polymorphic microsatellite locus occurs at higher frequency among affected compared to unaffected individuals for each lesion. As a result, gene loci recessively associated with each lesion were mapped on different chromosomal positions. We concluded that each of these lesions in MRL/lpr mice is under the control of a different set of genes, suggesting that the complex pathological manifestations of collagen disease result from polygenic inheritance.