Peter Raeymaekers

A new gene (DYX3) for dyslexia is located on chromosome 2

Developmental dyslexia is a specific reading disability affecting children and adults who otherwise possess normal intelligence, cognitive skills, and adequate schooling. Difficulties in spelling and reading may persist through adult life. Possible localisations of genes for dyslexia have been reported on chromosomes 15 (DYX1), 6p21.3-23 (DYX2), and 1p over the last 15 years. Only the localisation to 6p21.3-23 has been clearly confirmed and a genome search has not previously been carried out. We have investigated a large Norwegian family in which dyslexia is inherited as an autosomal dominant trait. A genome wide search for linkage with an average 20 cM marker density was initiated in 36 of the 80 family members. The linkage analysis was performed under three different diagnostic models. Linkage analysis in the family identified a region in 2p15-p16 which cosegregated with dyslexia. Maximum lod scores of 3.54, 2.92, and 4.32 for the three different diagnostic models were obtained. These results were confirmed by a non-parametric multipoint GENEHUNTER analysis in which the most likely placement of the gene was in a 4 cM interval between markers D2S2352 and D2S1337. Localisation of a gene for dyslexia to 2p15-16, together with the confirmed linkage to 6p21.3-23, constitute strong evidence for genetic heterogeneity in dyslexia. Since no gene for dyslexia has been isolated, little is known about the molecular processes involved. The isolation and molecular characterisation of this newly reported gene on chromosome 2 (DYX3) andDYX1 will thus provide new and exciting insights into the processes involved in reading and spelling.

A European multicenter association study of HTR2A receptor polymorphism in bipolar affective disorder

The available data on the role of 5-HT in a variety of behaviors support the hypothesis that a dysfunction in brain serotoninergic system activity contributes to vulnerability to major depression. The diversity in the electrophysiological actions of 5-HT in the central nervous system can now be categorized according to receptor subtypes and their respective effector mechanisms. In particular, the implication of central postsynaptic 5-HT2A receptor in affective disorders has been supported by findings consistent with the hypothesis of 5-HT2A receptor up-regulation in depression. For these reasons, the 5-HT2A receptor (HTR2A) gene can be considered as a candidate gene in bipolar affective disorder (BPAD). We tested the possible genetic contribution of the polymorphic DNA variation T102C in exon 1 of HTR2A (chromosome 13q14-21) gene in a large European multicentric case-control sample. Allele and genotype frequencies, as well as homo-heterozygote distributions were compared between the two groups of 309 bipolar affective disorder patients and 309 matched controls. No significant differences were observed in the allelic and genotypic (also for homo-heterozygote) distribution between BPAD and controls. These results indicate that, in our sample, the 5-HT2A receptor polymorphism studied is unlikely to play a major role in the genetic susceptibility to BPAD. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:136-140, 2000.

ASSIGNMENT OF X-LINKED HYDROCEPHALUS TO XQ28 BY LINKAGE ANALYSIS

X-linked recessive hydrocephalus (HSAS) occurs at a frequency of approximately 1 per 30,000 male births and consists of hydrocephalus, stenosis of the aqueduct of Sylvius, mental retardation, spastic paraparesis, and clasped thumbs. Prenatal diagnosis of affected males by ultrasonographic detection of hydrocephalus is unreliable because hydrocephalus may be absent antenatally. Furthermore, carrier detection in females is not possible because they are asymptomatic. Using four families segregating HSAS, we performed linkage analysis with a panel of X-linked probes that detect restriction fragment length polymorphisms. We report here that HSAS, in all tested families, is closely linked to marker loci mapping in Xq28 (DXS52, lod = 6.52 at theta of 0.03; F8, lod = 4.32 at theta of 0.00; DXS15, lod = 3.40 at theta of 0.00). These data assign HSAS to the gene-dense chromosomal band Xq28 and allow for both prenatal diagnosis and carrier detection by linkage analysis.

Linkage analysis of distal hereditary motor neuropathy type II (distal HMN II) in a single pedigree

We describe a six generation family affected with the autosomal dominant form of distal hereditary motor neuropathy type II (distal HMN II). The distal HMN shows similarities with the hereditary motor and sensory neuropathies type I and II (HMSN I and HMSN II) or Charcot-Marie-Tooth disease type 1 and 2 (CMT 1 and CMT 2) and with some proximal HMN or spinal muscular atrophies (SMA). Gene loci have been assigned to chromosomes 1q, 17p, and 19q for CMT 1 and to chromosome 5q for recessive SMA. In this study we excluded all four regions for the presence of distal HMN II, indicating that this neuropathy is genetically different from CMT 1 and recessive SMA.

Linkage of mood disorders with D2, D3 and TH genes: a multicenter study

BACKGROUND It has been suggested that the dopaminergic system is involved in the pathophysiology of mood disorders. We conducted a multicenter study of families with mood disorders, to investigate a possible linkage with genes coding for dopamine receptor D2, dopamine receptor D3 and tyrosine hydroxylase (TH). METHODS Twenty three mood disorder pedigrees collected within the framework of the European Collaborative Project on Affective Disorders were analyzed with parametric and non-parametric linkage methods. Various potential phenotypes were considered, from a narrow (only bipolar as affected) to a broad (bipolar+major depressive+schizoaffective disorders) definition of affection status. RESULTS Parametric analyses excluded linkage for all the candidate genes, even though small positive LOD (Limit of Detection) scores were observed for TH in three families. Non-parametric analyses yielded negative results for all markers. CONCLUSION The D2 and D3 dopamine receptors were, therefore, not a major liability factor for mood disorders in our sample, whereas TH may play a role in a subgroup of patients.

The Duffy blood group is linked to the α-spectrin locus in a large pedigree with autosomal dominant inheritance of Charcot-marie-Tooth disease type 1

SummaryThe α-spectrin locus (SPTA) on chromsome 1 maps to 1q22–q25 and α-spectrin specific probes detect restriction fragment length polymorphisms (RFLPs) with the endonucleases MspI and PvuII. The Duffy blood group (FY) has been mapped to the 1p21–q23 region. We found positive linkage between the α-spectrin and the Duffy loci with a maximal Lod score of 3.81 at θ=0.0 using the computer program MLINK. This indicates that both loci are very closely linked and probably localized to 1q22–q23.

Mapping of the gene for X-linked liver glycogenosis due to phosphorylase kinase deficiency to human chromosome region Xp22

X-linked liver glycogenosis (XLG) is a glycogenosis due to deficient activity of phosphorylase kinase (PHK) in liver. PHK consists of four different subunits, alpha, beta, gamma, and delta. Although it is unknown whether liver and muscle PHK subunits are encoded by the same genes, the muscle alpha subunit (PHKA) gene was a likely candidate gene for the mutation responsible for this X-linked liver glycogenosis as it was assigned to the X chromosome at q12-q13. Linkage analysis with X-chromosomal polymorphic DNA markers was performed in two families segregating XLG. First, multipoint linkage analysis excluded the muscle PHKA region as the site of the XLG mutation. Second, evidence was obtained for linkage between the XLG locus and DXS197, DXS43, DXS16, and DXS9 with two-point peak lod scores Zmax = 6.64, 3.75, 1.30, and 0.88, all at theta max = 0.00, respectively. Multipoint linkage results and analysis of recombinational events indicated that the mutation responsible for XLG is located in Xp22 between DXS143 and DXS41.

Manic-Depressive Illness and Linkage Reanalysis in the Xq27-Xq28 Region of Chromosome X

Inconsistent findings in X linkage studies of manic-depressive illness (MDI) have been ascribed to the presence of phenotypic uncertainties (incomplete penetrance), considerable variation in form and severity of MDI, and the likely presence of phenocopies (or false positives). In order to address some of these issues, previous X linkage data with colour blindness, glucose-6-phosphate dehydrogenase deficiency, and blood coagulation factor IX (F9) markers were reanalysed using a narrow and a broad definition of MDI. Our results confirm the X-linked hypothesis for MDI genetic transmission when controlling for diagnostic variation. The lod score (log of odds ratio) is reduced for a more conservative definition of the disease, but nevertheless remains significant. However, conclusive linkage between the MDI gene and the F9 gene in the Xq27 region is not maintained in our series. Our findings emphasize the need to reanalyse previous genetic data with more sophisticated diagnostic and statistical techniques.

Absence of linkage with the Duffy blood group in a family with Charcot-Marie-Tooth neuropathy

We report a large Belgian family with Charcot-Marie-Tooth disease (CMT) or hereditary motor and sensory neuropathy type I (HMSN-I). The pedigree consists of 5 generations with 350 family members comprising 42 patients. The disease is transmitted according to an autosomal dominant inheritance pattern. Several HMSN-I families have been reported to be closely linked to the Duffy blood group marker on chromosome 1. These families were designated HMSN-Ib families, opposed to the HMSN-Ia families which do not show evidence for such a linkage. Therefore we examined our family for the Duffy linkage relationship. We found no evidence for a strong linkage of the disease to the Duffy blood group locus, indicating that this family is of genetic subtype Ia.

DNA fingerprints revealing common and divergent human DNA methylation patterns

We compared DNA fingerprints of different cell populations from the same individuals, after separate digestion with the isoschizomers MboI and Sau3A. Methylation differences were observed within every individual when comparing fingerprints of Sau3A‐ with MboI‐digested DNA, and of Sau3A‐digested sperm with somatic DNA. In some cases, differences were also detected between fingerprints of Sau3A‐digested somatic DNA originating from various cell sources. Methylation patterns common to all cell populations examined, including the germline, were observed with a higher frequency than divergent ones. These ‘common methylations’ are most likely to find their origin during early embryogenesis.