RASopathies are autosomal dominant disorders caused by mutations in more than 10 known genes that regulate the RAS/MAPK pathway. Noonan syndrome (NS) is a RASopathy characterized by a distinctive facial appearance, musculoskeletal abnormalities, and congenital heart defects. We have recently identified mutations in RIT1 in patients with NS. To delineate the clinical manifestations in RIT1 mutation-positive patients, we further performed a RIT1 analysis in RASopathy patients and identified 7 RIT1 mutations, including two novel mutations, p.A77S and p.A77T, in 14 of 186 patients. Perinatal abnormalities, including nuchal translucency, fetal hydrops, pleural effusion, or chylothorax and congenital heart defects, are observed in all RIT1 mutation-positive patients. Luciferase assays in NIH 3T3 cells demonstrated that the newly identified RIT1 mutants, including p.A77S and p.A77T, and the previously identified p.F82V, p.T83P, p.Y89H, and p.M90I, enhanced Elk1 transactivation. Genotype-phenotype correlation analyses of previously reported NS patients harboring RIT1, PTPN11, SOS1, RAF1, and KRAS revealed that hypertrophic cardiomyopathy (56 %) was more frequent in patients harboring a RIT1 mutation than in patients harboring PTPN11 (9 %) and SOS1 mutations (10 %). The rates of hypertrophic cardiomyopathy were similar between patients harboring RIT1 mutations and patients harboring RAF1 mutations (75 %). Short stature (52 %) was less prevalent in patients harboring RIT1 mutations than in patients harboring PTPN11 (71 %) and RAF1 (83 %) mutations. These results delineate the clinical manifestations of RIT1 mutation-positive NS patients: high frequencies of hypertrophic cardiomyopathy, atrial septal defects, and pulmonary stenosis; and lower frequencies of ptosis and short stature.
Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder caused by survival motor neuron gene mutations. Variant forms of SMA accompanied by additional clinical presentations have been classified as atypical SMA and are thought to be caused by variants in as yet unidentified causative genes. Here, we presented the clinical findings of two siblings with an SMA variant followed by progressive cerebral atrophy, and the results of whole-exome sequencing analyses of the family quartet that was performed to identify potential causative variants. We identified two candidate homozygous missense variants, R942Q in the tubulin-folding cofactor D (TBCD) gene and H250Q in the bromo-adjacent homology domain and coiled-coil containing 1 (BAHCC1) gene, located on chromosome 17q25.3 with an interval of 1.4 Mbp. The in silico analysis of both variants suggested that TBCD rather than BAHCC1 was likely the pathogenic gene (TBCD sensitivity, 0.68; specificity, 0.97; BAHCC1 sensitivity, 1.00; specificity, 0.00). Thus, our results show that TBCD is a likely novel candidate gene for atypical SMA with progressive cerebral atrophy. TBCD is predicted to have important functions on tubulin integrity in motor neurons as well as in the central nervous system.
Differential Effects of Aging, Drinking andExercise on Serum Cholesterol Levels Dependent on the PPARA-V227A Polymorphism: Hisao NAITO, e t a l . D e p a r t m e n t o f O c c u p a t i o n a l a n d Environmental Health, Nagoya University Graduate School of Medicine-Peroxisome proliferatoractivated receptor α (PPAR α) plays a pivotal role in lipid metabolism. Our previous study reported that PPARA-V227A was a major polymorphism in Japanese, which was associated with markedly lower serum total cholesterol (TC) levels, which were significantly affected by alcohol drinking compared to subjects with the wild-type (PPARA-WT) allele. However, serum lipids are also associated with aging and exercise frequency. The objective of the present study was to evaluate the relationship between PPARA-V227A and these factors. Genetic analysis of the polymorphism was performed in 1058 Japanese men and 281 women, and the relationship with aging, drinking and exercise on serum lipids was analyzed in 989 men and 245 women after exclusion criteria had been applied. In men, drinking increased high-density lipoprotein cholesterol (HDL-C) levels in both PPARA-WT and A227 carriers, but to a significantly higher degree in the latter. In women, TC and low-density lipoprotein cholesterol (LDL-C) levels in the A227 carriers drinking at least once a week were significantly higher than in PPARA-WT carriers. TC and LDL-C levels in males with PPARA-WT increased with aging regardless of drinking habit, while LDL-C levels in the A227 drinking carriers were significantly lower in 45-yr-old or older subjects than in 35-to 45-yr-olds. In addition, no effect of exercising was observed in the A227 carriers, while increase in the HDL-C of the PPARA-WT carriers was exercise frequency dependent. These results suggest that the influence of drinking, aging or exercise on TC, LDL-C and HDL-C levels in the A227 carriers may be different from those in the PPARA-WT subjects. (J Occup Health 2007; 49: 353-362)
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