Duchenne muscular dystrophy (DMD) is a progressive disease characterised by chronic muscle degeneration and inflammation. Our previously established DMD model rats (DMD rats) have a more severe disease phenotype than the broadly used mouse model. We aimed to investigate the role of senescence in DMD using DMD rats and patients. Senescence was induced in satellite cells and mesenchymal progenitor cells, owing to the increased expression of CDKN2A, p16- and p19-encoding gene. Genetic ablation of p16 in DMD rats dramatically restored body weight and muscle strength. Histological analysis showed a reduction of fibrotic and adipose tissues invading skeletal muscle, with increased muscle regeneration. Senolytic drug ABT263 prevented loss of body weight and muscle strength, and increased muscle regeneration in rats even at 8 months—the late stage of DMD. Moreover, senescence markers were highly expressed in the skeletal muscle of DMD patients. In situ hybridization of CDKN2A confirmed the expression of it in satellite cells and mesenchymal progenitor cells in patients with DMD. Collectively, these data provide new insights into the integral role of senescence in DMD progression.

Amelogenesis imperfecta (AI) is currently classified into 14 distinct subtypes based on various phenotypic criteria; however, the gene responsible for each phenotype has not been defined. We performed molecular genetic studies on a Japanese family with a possible autosomal-dominant form of AI. Previous studies have mapped an autosomal-dominant human AI locus to chromosome 4q11-q21, where two candidate genes, ameloblastin and enamelin, are located. We studied AI patients in this family, focusing on these genes, and found a mutation in the enamelin gene. The mutation detected was a heterozygous, single-G deletion within a series of 7 G residues at the exon 9-intron 9 boundary of the enamelin gene. The mutation was detected only in AI patients in the family and was not detected in other unaffected family members or control individuals. The male proband and his brother showed hypoplastic enamel in both their deciduous and permanent teeth, and their father showed local hypoplastic defects in the enamel of his permanent teeth. The clinical phenotype of these patients is similar to that of the first report of AI caused by an enamelin gene mutation. Thus, heterogeneous mutations in the enamelin gene are responsible for an autosomal-dominant hypoplastic form of AI.

Amelogenesis imperfecta (AI) is currently classified into 14 distinct subtypes based on various phenotypic criteria; however, the gene responsible for each phenotype has not been defined. We performed molecular genetic studies on a Japanese family with a possible autosomal-dominant form of AI. Previous studies have mapped an autosomal-dominant human AI locus to chromosome 4q11-q21, where two candidate genes, ameloblastin and enamelin, are located. We studied AI patients in this family, focusing on these genes, and found a mutation in the enamelin gene. The mutation detected was a heterozygous, single-G deletion within a series of 7 G residues at the exon 9-intron 9 boundary of the enamelin gene. The mutation was detected only in AI patients in the family and was not detected in other unaffected family members or control individuals. The male proband and his brother showed hypoplastic enamel in both their deciduous and permanent teeth, and their father showed local hypoplastic defects in the enamel of his permanent teeth. The clinical phenotype of these patients is similar to that of the first report of AI caused by an enamelin gene mutation. Thus, heterogeneous mutations in the enamelin gene are responsible for an autosomal-dominant hypoplastic form of AI.

Abstract. Path om orph ologic stud ies were car ried out on three cases of bovine diab etes mellitus with clinical signs o f polydip sia, polyuria, severe emac iation, glycosuria , persistent hyperglycemi a, and decreased glucose toleran ce. At necrop sy, two an imals had atro phy of th e pan creas, whereas other visce ral organs , includ ing the endocrine organs, showed no significa nt cha nges. Microscopically, there was atro phy an d reduced num bers of pan creati c islets acco mpa nied by int erl obular and interaci na r fibrosis and co mpensa tory enlargement of some rem ainin g islets. Lymphocytes were observed com mo nly around and within atro phic islets and occa siona lly aro und and within enlarged islets. Vac uolar degenerati on with occasiona l accumulation of glycogen granules was observe d in the /:i-cells of these enlarged islets. Immunohi stoch em ical stud ies of atro phic islets dem onstrated co m plete loss o f /:i-cells or only a few sma ll /:i-cells. Th ere also was a correspo ndi ng decrease in the number of cells that stai ned with anti-glucagon (a -cells) or anti-so ma tos tati n (o-cells) anti bodies. Th e vac uolated cells in the en larged islets stained strongly with anti-insulin antibody (/:i-cells). U ltrast ruc tura lly, the majority of cells in the atro phic islets had red uced cytoplasmic vo lume and few secre tory granules, features consiste nt with a -cells. In contras t, enlarged islets that had promi nent immunoh istochemi cal sta ini ng for insul in (/:i-cells) cons isted of /:i-cells with cytoso lic ede ma, m itochondrial swelling, d ilated smoo th endo plasmic reticulum, and redu ced numbers of or degranulated secreto ry granules. Th ese path omorphologic features found in catt le are simi lar to th ose found in ju venil e-on set insulin -depend ent diabetes mellitus in hum an beings and suggest aut oimmune involvement in d iabetes.

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