Phenotype of a homozygous CADASIL patient in comparison to 9 age-matched heterozygous patients with the same R133C Notch3 mutation

Background and Purpose-CADASIL is an autosomal dominant arteriopathy, characterized by multiple brain infarcts, cognitive decline, and finally dementia, which is caused by mutations in Notch3 gene encoding a Notch3 receptor protein. We describe the clinical, neuropsychological, imaging, genetic, and skin biopsy findings in a CADASIL patient homozygous for the C475T mutation resulting in R133C amino acid substitution, in comparison to 9 age-matched heterozygous patients with the same mutation. Methods-The patients were examined clinically and neuropsychologically and with MRI and positron emission tomography for assessment of cerebral blood flow. The gene defect was analyzed by sequencing the products of polymerase chain reaction of exons 3 and 4 of the Notch3 gene. Dermal arteries were analyzed electron microscopically. Results-The homozygous patient had his first-ever stroke at age 28 years. This is markedly earlier than the average, but the patient's heterozygous son had his first transient ischemic attack-like episode at the same age and another heterozygous patient had his first-ever stroke when only 2 years older. He was neuropsychologically more severely deteriorated than all but 1 of the heterozygous patients. These 2 patients had the most severe (confluent grade D) white matter MRI changes. Positron emission tomography showed markedly reduced cerebral blood flow. Skin biopsy revealed profuse deposits of granular osmiophilic material. The progression of disease in the homozygous case was, however, slower than in the most severely affected heterozygous patient. Conclusions-Our homozygous patient's phenotype is within the clinical spectrum of CADASIL, although at its severe end. Thus, CADASIL may follow the classic definition of a dominant disease, according to which the heterozygous and homozygous patients are clinically indistinguishable.Peer reviewe

Absence of the genetic variant Val(79)Met in human chorionic gonadotropin-beta gene 5 in five European populations

Chorionic gonadotropin (CG) is an essential signal in establishment and maintenance of pregnancy in humans and higher primates. A G-to-A transition in exon 3 of human CGbeta gene 5, changing the naturally occurring valine residue to methionine in codon 79 (Val(79)Met) has been reported at carrier frequency 4.2% in a random population from the Midwest of the United States. The biological activity of the variant hCG was similar to that of wild-type (WT) hCG. However, the Val(79)Met beta-subunit displayed impaired ability to assemble with alpha-subunit, and the amount of hCG alpha/beta heterodimers formed and secreted by transfected cells was seriously impaired in the previous study. Because of these functional implications we found it important to study the occurrence of the Val(79)Met hCGbeta variant in other populations. By using a PCR-RFLP method, a search for the Val(79)Met hCGbeta variant was carried out on a total of 580 DNA samples from five European populations (Finland, Denmark, Greece, Germany and the UK). The results demonstrated an absence of the polymorphism in these populations. Hence, the naturally occurring variant (Val(79)Met) of the hCGbeta gene 5, found previously at high frequency in the US, is clearly less common, or absent, in the European populations studied

Classification of European mtDNAs from an analysis of three European populations

Mitochondrial DNA (mtDNA) sequence variation was examined in Finns, Swedes and Tuscans by PCR amplification and restriction analysis. About 99% of the mtDNAs were subsumed within 10 mtDNA haplogroups (H, I, J, K, M, T, U, V, W, and X) suggesting that the identified haplogroups could encompass virtually all European mtDNAs. Because both hypervariable segments of the mtDNA control region were previously sequenced in the Tuscan samples, the mtDNA haplogroups and control region sequences could be compared. Using a combination of haplogroup-specific restriction site changes and control region nucleotide substitutions, the distribution of the haplogroups was surveyed through the published restriction site polymorphism and control region sequence data of Caucasoids. This supported the conclusion that most haplogroups observed in Europe are Caucasoid-specific, and that at least some of them occur at varying frequencies in different Caucasoid populations. The classification of almost all European mtDNA variation in a number of well defined haplogroups could provide additional insights about the origin and relationships of Caucasoid populations and the process of human colonization of Europe, and is valuable for the definition of the role played by mtDNA backgrounds in the expression of pathological mtDNA mutations

mtDNA analysis reveals a major late Paleolithic population expansion from southwestern to northeastern Europe

mtDNA sequence variation was studied in 419 individuals from nine Eurasian populations, by high-resolution RFLP analysis, and it was followed by sequencing of the control region of a subset of these mtDNAs and a detailed survey of previously published data from numerous other European populations. This analysis revealed that a major Paleolithic population expansion from the "Atlantic zone" (southwestern Europe) occurred 10,000-15,000 years ago, after the Last Glacial Maximum. As an mtDNA marker for this expansion we identified haplogroup V, an autochthonous European haplogroup, which most likely originated in the northern Iberian peninsula or southwestern France at about the time of the Younger Dryas. Its sister haplogroup, H, which is distributed throughout the entire range of Caucasoid populations and which originated in the Near East approximately 25,000-30,000 years ago, also took part in this expansion, thus rendering it by far the most frequent (40%-60%) haplogroup in western Europe. Subsequent migrations after the Younger Dryas eventually carried those "Atlantic" mtDNAs into central and northern Europe. This scenario, already implied by archaeological records, is given overwhelming support from both the distribution of the autochthonous European Y chromosome type 15, as detected by the probes 49a/f, and the synthetic maps of nuclear data

Clinical expression of Leber hereditary optic neuropathy is affected by the mitochondrial DNA–haplogroup background

Leber hereditary optic neuropathy (LHON) is due primarily to one of three common point mutations of mitochondrial DNA (mtDNA), but the incomplete penetrance implicates additional genetic or environmental factors in the pathophysiology of the disorder. Both the 11778G-->A and 14484T-->C LHON mutations are preferentially found on a specific mtDNA genetic background, but 3460G-->A is not. However, there is no clear evidence that any background influences clinical penetrance in any of these mutations. By studying 3,613 subjects from 159 LHON-affected pedigrees, we show that the risk of visual failure is greater when the 11778G-->A or 14484T-->C mutations are present in specific subgroups of haplogroup J (J2 for 11778G-->A and J1 for 14484T-->C) and when the 3460G-->A mutation is present in haplogroup K. By contrast, the risk of visual failure is significantly less when 11778G-->A occurs in haplogroup H. Substitutions on MTCYB provide an explanation for these findings, which demonstrate that common genetic variants have a marked effect on the expression of an ostensibly monogenic mtDNA disorder

Estimation of the mutation frequencies in Charcot-Marie-Tooth disease type 1 and hereditary neuropathy with liability to pressure palsies: a European collaborative study

A European collaboration on Charcot-Marie-Tooth type 1 (CMT1) disease and hereditary neuropathy with liability to pressure palsies (HNPP) was established to estimate the duplication and deletion frequency, respectively, on chromosome 17p11.2 and to make an inventory of mutations in the myelin genes, peripheral myelin protein 22 (PMP22), myelin protein zero (MPZ) and connexin 32 (Cx32) located on chromosomes 17p11.2, 1q21-q23 and Xq13.1, respectively. In 70.7% of 819 unrelated CMT1 patients, the 17p11.2 duplication was present. In 84.0% of 156 unrelated HNPP patients, the 17p11.2 deletion was present. In the nonduplicated CMT1 patients, several different mutations were identified in the myelin genes PMP22, MPZ and Cx32

Estimation of the mutation frequencies in Charcot-Marie-Tooth disease type 1 and hereditary neuropathy with liability to pressure palsies: a European collaborative study

A European collaboration on Charcot-Marie-Tooth type 1 (CMT1) disease and hereditary neuropathy with liability to pressure palsies (HNPP) was established to estimate the duplication and deletion frequency, respectively, on chromosome 17p11.2 and to make an inventory of mutations in the myelin genes, peripheral myelin protein 22 (PMP22), myelin protein zero (MPZ) and connexin 32 (Cx32) located on chromosomes 17p11.2, 1q21-q23 and Xq13.1, respectively. In 70.7% of 819 unrelated CMT1 patients, the 17p11.2 duplication was present. In 84.0% of 156 unrelated HNPP patients, the 17p11.2 deletion was present. In the nonduplicated CMT1 patients, several different mutations were identified in the myelin genes PMP22, MPZ and Cx32