Mutations in the fused in sarcoma (FUS, also known as translated in liposarcoma) gene have been recently discovered to be associated with familial amyotrophic lateral sclerosis (FALS) in African, European and American populations. In a Japanese family with FALS, we found the R521C FUS mutation, which has been reported to be found in various ethnic backgrounds. The family history revealed 23 patients with FALS among 46 family members, suggesting a 100% penetrance rate. They developed muscle weakness at an average age of 35.3 years, followed by dysarthria, dysphagia, spasticity and muscle atrophy. The average age of death was 37.2 years. Neuropathological examination of the index case revealed remarkable atrophy of the brainstem tegmentum characterized by cytoplasmic basophilic inclusion bodies in the neurons of the brainstem. We screened 40 FALS families in Japan and found 4 mutations (S513P, K510E, R514S, H517P) in exon 14 and 15 of FUS. Even in Asian races, FALS with FUS mutations may have the common characteristics of early onset, rapid progress and high penetrance rate, although in patients with the S513P mutation it was late-onset. Degeneration in multiple systems and cytoplasmic basophilic inclusion bodies were found in the autopsied cases. 3 Very recently, two groups of investigators reported the autosomal dominant form of FALS caused by fused in sarcoma (FUS) mutations, 4,5 following several reports of both familial and sporadic cases from Europe. 6-9 FUS is a nucleoprotein that functions in DNA and RNA metabolism. 10 In this study, we found a large Japanese FALS family with mutations in the FUS gene with the characteristics of early onset. In addition, we report four mutations of the FUS gene in Japanese FALS. CASE REPORT OF THE INDEX CASEThe patient (indicated by arrow in Figure 1a) was a Japanese man with autosomal dominant hereditary burden as described in a previous report. 11 His family history revealed 23 patients with FALS over four generations (Figure 1a). He developed muscle weakness of the distal part of the right upper extremity at age 30, followed by dysarthria, dysphagia, muscle weakness and atrophy in the four extremities, spasticity, hyperreflexia and Babinski's sign. His sensory, cerebellar and higher cortical functions were not affected. At age 31 (17 months after onset) he needed ventilatory support. At age 40, he died of bronchopneumonia. MATERIALS AND METHODSAll patients of FALS without the superoxide dismutase 1 mutation and healthy controls provided informed consent, after which DNA extraction and genotyping were performed using standard protocols as described elsewhere. 12 We sequenced all exons in 40 unrelated FALS families with the characteristics of an autosomal dominant trait in Japan. Sections of 5 mm thickness were taken from the midbrain of the index case and stained as described elsewhere. 5 Rabbit polyclonal anti-TDP-43 (ProteinTech, Chicago, IL, USA) and rabbit polyclonal anti-ubiquitin (Abcam, Cambridge, MA, USA) antibodies were used. The study was approved by the ethic...

A series of key amino acids involved in Ins(1,4,5)P3 (InsP3) binding and catalytic activity of rat brain InsP3 3-kinase has been identified. The catalytic domain is at the C-terminal end and restricted to a maximum of 275 amino acids [Takazawa and Erneux (1991) Biochem. J. 280, 125-129]. In this study, newly prepared 5'-deletion and site-directed mutants have been compared both for InsP3 binding and InsP3 3-kinase activity. When the protein was expressed from L259 to R459, the activity was lost but InsP3 binding was conserved. Another deletion mutant that had lost only four amino acids after L259 had lost InsP3 binding, and this finding suggests that these residues (i.e. L259DCK262) are involved in InsP3 binding. To further support the data, we have produced two mutants by site-directed mutagenesis on residues C261 and K262. The two new enzymes were designated M4 (C261S) and M5 (K262A). M4 showed similar Vmax and Km values for InsP3 and ATP to wild-type enzyme. In contrast, M5 was totally inactive but had kept the ability to bind to calmodulin-Sepharose. C-terminal deletion mutants that had lost five, seven or nine amino acids showed a large decrease in InsP3 binding and InsP3 3-kinase activity. One mutant that had lost five amino acids (M2) was purified to apparent homogeneity: Km values for both substrates appeared unchanged but Vmax was decreased approx. 40-fold compared with the wild-type enzyme. The results indicate that (1) a positively charged amino acid residue K262 is essential for InsP3 binding and (2) amino acids at the C-terminal end of the protein are necessary to act as a catalyst in the InsP3 3-kinase reaction.

No abstract

Histologic examination of sural nerve of a 32-year-old man with an aggressive polyneuropathy associated with autonomic failure demonstrated amyloid deposition, and familial amyloidotic polyneuropathy (FAP) was diagnosed. Immunohistochemical staining showed transthyretin (TTR) staining of the amyloid deposits in nerve. Sequencing revealed G to A transition in the codon 54 causing TTR Lys 54. This is a new variant TTR associated with aggressive FAP.

No abstract

No abstract

Pentalogy of Cantrell is a rare congenital anomaly characterized by a combination of severe defects in the middle of the chest and abdomen including intracardiac defects. Survival rate after cardiac surgery is extremely low. We present a successful staged complete repair of an omphalocele, a ventricular septal defect and a sternal defect in a case of pentalogy of Cantrell.

Conjunctival squamous cell carcinoma developed in a 51-year-old man 40 years after he had enucleation of his left eye because of an explosion injury. He had worn several ocular prostheses for more than 40 years. Recently he had noticed an increasing sanguineous conjunctival discharge, a foreign body sensation, and swelling of his left lower eyelid. Incisional biopsies of an underlying conjunctival mass revealed squamous cell carcinoma. His work history did not involve exposure to radiation, chemicals, or the sun. The authors concluded that squamous cell carcinoma in this case was caused by chronic irritation as the result of long-standing use of a poorly fitting ocular prosthesis.