Masaki Komatsu

Mutations of the NOG gene in individuals with proximal symphalangism and multiple synostosis syndrome

Proximal symphalangism is an autosomal‐dominant disorder with ankylosis of the proximal interphalangeal joints, carpal and tarsal bone fusion, and conductive deafness. These symptoms are shared by another disorder of joint morphogenesis, multiple synostoses syndrome. Recently, it was reported that both disorders were caused by heterozygous mutations of the human noggin gene (NOG). To date, seven mutations of NOG have been identified from unrelated families affected with joint morphogenesis. To characterize the molecular lesions of proximal symphalangism, we performed analyses of NOG in three Japanese individuals with proximal symphalangism. We found three novel mutations: g.551G>A (C184Y) in a sporadic case of symphalangism, g.386T>A (L129X) in a familial case of symphalangism, and a g.58delC (frameshift) in a family with multiple synostosis syndrome. Characteristic genotype–phenotype correlations have not been recognized from the mutations in the NOG gene.

An exonic mutation of the GH-1 gene causing familial isolated growth hormone deficiency type II

A heterozygous base change was identified in exon 3 of the growth hormone (GH)‐1 gene in a Japanese family with autosomal dominant GH deficiency. All of the patients from this family had a heterozygous G to T transversion at the first 5′‐site nucleotide of exon 3. Analysis of the GH‐1 cDNA, synthesized from lymphoblasts of the patients, revealed an abnormal shorter transcript as well as a normal‐sized transcript. Direct sequencing of this abnormal transcript showed that the transcript completely lacked exon 3. In familial isolated GH deficiency (IGHD) type II, several heterozygous mutations have been reported at the donor splice site in intron 3 of the GH‐1 gene or inside intron 3, which causes aberrant GH messenger RNA splicing, resulting in the deletion of exon 3. This deletion causes a lack of amino acid residues 32–71 in the mature GH protein. This mutant GH is well‐known to exert a dominant negative effect on the secretion of mature normal GH protein. Thus, in the subject family, a heterozygous G‐to‐T transversion at the first nucleotide of the exon 3 deletes exon 3 in mature GH mRNA and causes GH deficiency. The present authors suggest that the first nucleotide of exon 3 is critical for the splicing of GH‐1 mRNA.

Ala/Thr60 variant of the Leydig insulin-like hormone is not associated with cryptorchidism in the Japanese population.

Abstract 
 Background : Leydig insulin‐like hormone (Insl3), a member of the insulin‐like superfamily, is specifically expressed in Leydig cells of fetal and postnatal murine testis. Recently, the absence of the Insl3 gene has been reported to result in bilateral cryptorchidism in male mice and it has been suggested that mutations of the INSL3 gene may cause cryptorchidism in humans.

Evidence for the association of ultraviolet-C and H2O2-induced apoptosis with acid sphingomyelinase activation

Ceramide appears to be a potent second messenger implicated in the regulation of diverse cellular processes such as cell growth and differentiation, gene transcription, ligand binding, and cell death. Environmental stress-induced apoptosis is believed to be associated with the sphingomyelin degradation pathway, which generates ceramide as a second messenger in initiating the apoptosis response. To date, two distinct sphingomyelinases, a lysosomal acid sphingomyelinase (ASM), which is deficient in patients affected with types A and B Niemann-Pick disease (NPD), and a neutral, magnesium-dependent sphingomyelinase (NSM), are candidate enzymes which respond to apoptotic stimulations and cause sphingomyelin hydrolysis and subsequent ceramide generation. Using Epstein-Barr virus (EBV)-transformed lymphoblast cells from type A NPD patient which have defined splicing site mutation in the ASM gene, we showed that ASM-deficient cells were defective in ultraviolet-C (UV-C) and hydrogen peroxide (H(2)O(2)) induced apoptosis. As another induction of apoptosis, we exposed this cell line to serum starvation which influences to p53 expression and leads to apoptosis. There were no differences by the degree of apoptosis between ASM-deficient lymphoblast cells and normal lymphoblast cells. These results are evidence that ASM plays one of the important roles in apoptosis induction by UV-C and H(2)O(2).

Familial mediterranean fever medicated with an herbal medicine in Japan.

Familial mediterranean fever (FMF) is an autosomal recessive disorder resulting from the genetic mutations in the FMF gene ( MEFV ) and characterized by self-limited periodic fever and serositis, often associated with renal amyloidosis. The inflammatory attacks of FMF can be effectively treated with colchicine. More than 90% of FMF patients have a complete remission or a marked amelioration of attacks if they take the colchicine. 1 However, attention should be paid to the side-effects of colchicine use. We report here a rare Japanese case of FMF where an herbal medicine, ‘ShoSaiko-To (TJ-9)’, was effective for prophylaxis of the attacks. In addition, we report that the E148Q, which was reported as a common founder mutation for FMF, is a normal variant of the MEFV gene among Japanese.