Masashi Miyake

An ancient retrotransposal insertion causes Fukuyama-type congenital muscular dystrophy

Fukuyama-type congenital muscular dystrophy (FCMD), one of the most common autosomal recessive disorders in Japan (incidence is 0.7–1.2 per 10,000 births), is characterized by congenital muscular dystrophy associated with brain malformation (micro-polygria) due to a defect in the migration of neurons. We previously mapped the FCMD gene to a region of less than 100 kilobases which included the marker locus D9S2107 on chromosome 9q31 (refs 2–4). We have also described a haplotype that is shared by more than 80% of FCMD chromosomes, indicating that most chromosomes bearing the FCMD mutation could be derived from a single ancestor. Here we report that there is a retrotransposal insertion of tandemly repeated sequences within this candidate-gene interval in all FCMD chromosomes carrying the founder haplotype (87%). The inserted sequence is about 3 kilobases long and is located in the 3′ untranslated region of a gene encoding a new 461-amino-acid protein. This gene is expressed in various tissues in normal individuals, but not in FCMD patients who carry the insertion. Two independent point mutations confirm that mutation of this gene is responsible for FCMD. The predicted protein, which we term fukutin, contains an amino-terminal signal sequence, which together with results from transfection experiments suggests that fukutin is a secreted protein. To our knowledge, FCMD is the first human disease to be caused by an ancient retrotransposal integration.

Founder-haplotype analysis in Fukuyama-type congenital muscular dystrophy (FCMD)

Abstract Fukuyama-type congenital muscular dystrophy (FCMD) is an autosomal recessive, severe muscular dystrophy associated with brain anomalies. After our initial mapping of the FCMD locus to 9q31–33, we performed linkage disequilibrium analysis, which led us to suspect that the FCMD gene lay within a region of less than 100 kb containing D9S2107. In the present study, we developed two new microsatellites (D9S2170 and D9S2171) in close vicinity to D9S2107 and examined haplotypes of FCMD chromosomes by using four markers (cen-D9S2105-D9S2170-D9S2171-D9S2107-tel). As 82% of the FCMD chromosomes that we examined shared the founder haplotype (138–192–147–183) and 94% of the FCMD patients in our panel carried founder haplotypes on one or both chromosomes, the data supported the hypothesis of a single founder of this disease in the Japanese population. Eight haplotypes different from the founder’s were observed in FCMD chromosomes, indicating that eight different FCMD mutations in addition to the founder’s have occurred in Japan. Moreover, we have detected several historical recombinations that have disrupted the founder haplotype at D9S2105 or D9S2170 and conclude that the FCMD gene is probably located just centromeric to D9S2170.

A STATISTICAL SURVEY OF DEEP FUNGUS INFECTION IN JAPAN

The authors report a statistical review of 546 cases of deep fungus infection which were observed in human post‐mortem materials. The materials were collected from 67,741 necropsy cases examined at the departments of pathology of 45 medical schools and three major hospitals in Japan between 1948 and 1961. The overall incidence of deep fungus infection was 0.8 per cent. The major types of infection were candidiasis, aspergillosis, cryptococcosis, actinomycosis and mucormycosis, in this order. All the geographic regions of deep fungus infection were represented. Apparent incident rates were high in the Kanto District which has many medical college hospitals and low in the Hokkaido area where the climate is rather cool. The yearly frequency, age distribution, site of infection and underlying conditions of the major types of fungus infection in Japan was described. From the analysis of the factors, it was concluded that the increase in number of cases with deep fungus infection was based not only upon the use of antibiotic and steroid therapy, but also on the increasing interest in fungus infection and the recent progress of investigating methods.

Dinucleotide repeat polymorphism on chromosome 9q32

SummaryA new microsatellite was developed from a cosmid clone (cCI9-246) assigned to human chromosome 9q32.

TISSUE IRON IN TOKYO, JAPAN COMPARISON WITH WESTERN COUNTRIES*

The most characteristic feature of hemochromatosis is increased tissue iron, which is usually demonstrated by histological staining or by chemical measurement. The tissue which is most often sampled for the evaluation of excess iron is the liver, because it is accessible by needle biopsy. In recent years several studies have been made in which asymptomatic relatives of patients with “idiopathic” hemochromatosis subjected to needle biopsy of the liverl-39 21) have had histologically stainable iron in the liver. This has been considered to be an abnormal finding and attributed to an inherited disorder of iron metabolism. This interpretation has been questioned, howevere), because more information is needed about the amounts of histological and chemical hepatic iron in “normal” or unselected persons who are not related to patients with idiopathic hemochromatosis, and in autopsy and liver biopsy investigations in the United StateslTt 181, IsraelT), and South Africas) stainable hepatic iron was found to be common. The present investigation was carried out in Japan to learn whether the finings were similar to western countries. Dietary conditions in Japan differ from most western countries. Less animal protein and fat are consumed. In addition, idiopathic hemochromatosis is more rare in Japan, a rate of approximately 32 per 100,000 autopsies compared with approximately 178 per 100,000 autopsies in the United Stateso).

Morphological Features and Physical Analysis of Causative Factors

Materials from 213 autopsy cases collected by the Pathology Team of the Special Committee for Investigation of Effects of Atomic Bombs, the National Science Council of Japan, were reviewed and sequence of the events, especially in the bone marrow from cases dead between a few days and 120 days after the exposures, was discussed in the light of newer knowledges in radiation pathology. The regeneration of the hematopoiesis in the irradiated bone marrows appeared to initiate from some surviving differentiated marrow cells and not from the so‐called stem cells. Distorsion of the bone‐marrow structures may have some bearing to abnormal regeneration, hyperplasia and neoplasia of the marrow elements.

A Histopathological Study of Infectious Hepatitis with Needle Biopsy Materials, Especially a Cytological and Microspectrophotometric Observation

It has been widely accepted that infectious hepatitis is a self-directing disease and its pathogen is a virus.(l)*(e)l(s) Recently in Japan, there was an outbreak of infectious hepatitis in Okayama Prefecture (69 patients and its mortality was 13 per cent),(4) and isolation of its virus has been performed.(5)~(6) At the 4th Meeting of the International Society of Geographic Pathology, infectious hepatitis was the main subject, and many detailed studies were reported and discussed. The authors were fortunate in obtaining the opportunity to study 10 cases of infectious hepatitis in the Tokyo area. Needle biopsy materials of the liver were taken, and the materials were investigated histopathologically, with special stress layed on cytological and microspectrophotometric observations.