Understanding the influence of both genetics and environment on human health, especially early in life, is essential for shaping long-term health. Here, we utilize a nationwide prospective birth cohort, the Japan Environment and Children's Study (JECS), to conduct a large-scale population-based genetic study using biannual questionnaire surveys and biological and physical measurements collected from both parents and their children since the participant mothers were pregnant. Analyses of genome-wide genotyping for 80,638 child participants with parental consent and sufficient DNA from cord blood samples represent the genetic diversity of the general population in Japan. Systematic genome-wide association studies of 1,163 child health and developmental traits (including, e.g., food allergy, anthropometry measurements or ASQ-3 developmental screening) and parental environmental exposure traits (including, e.g., mercury or PFAS exposure) identify 4,985 common genomic loci (of which 1,885 loci passed the phenome-wide significant P=4.3 x 10^(-11)), of which 25% of loci represent novel associations not previously reported. Additional longitudinal GWAS of BMI using Gaussian process regression identified 66 novel dynamic genetic associations along child development. In addition, genetic correlation analysis suggested some evidence that maternal environmental exposures during pregnancy influence child traits at birth. Together with studies of environmental exposures and genetic risk factors, across time and multiple outcomes, these demonstrate the uniqueness and value of the JECS data.
Spinal muscular atrophy (SMA) is a genetic neuromuscular disorder that results in progressive muscle atrophy and weakness. As new therapies for SMA have been developed, newborn screening for SMA can lead to early diagnosis and treatment. The objective of this study was to gather the general population’s view on screening of SMA in newborns in Japan. A questionnaire survey was conducted on two general population groups in Japan. A total of 269 valid responses were obtained. In the general population, about half of the participants had no knowledge about SMA, and more than 90% did not know about new therapies for SMA. Conversely, more than 95% of the general population agreed with screening newborns for SMA because they believed that early diagnosis was important, and treatments were available. This study revealed that the general population in Japan mostly agreed with screening for SMA in newborns even though they did not know much about SMA. Newborn screening for SMA is promising, but it is in very early stages. Therefore, SMA newborn screening should be performed with sufficient preparation and consideration in order to have a positive impact on SMA patients and their families.
Duchenne muscular dystrophy (DMD) is the most common form of inherited muscle disease and is characterized by progressive muscle wasting ultimately resulting in death of the patients in their twenties. DMD is characterized by a deficiency of the muscle dystrophin as a result of mutations in the dystrophin gene. Currently, no effective treatment for DMD is available. Two promising treatments strategies have been proposed specifically for correcting the mutations in the dystrophin gene. Induction of exon skipping using antisense oligonucleotides is expected to correct the out-of-frame mutation into in-frame mutation of the translational reading frame of dystrophin mRNA. This strategy enables the production of truncated dystrophin production in DMD patients with out-of-frame exon-deletion mutations in the dystrophin gene. Our first treatment with antisense oligonucleotides against exon 19 was successful and resulted in the production of dystrophin in the skeletal muscle of a DMD patient with exon 20 deletion. It is anticipated that exon skipping will be applied extensively for the correction of deletion mutations. Induction of the read-through effect using gentamycin or PTC124 is expected to produce dystrophin in DMD patients with nonsense mutation. The treatment with PTC124 is currently under clinical trial. In this review, these treatments strategies have been summarized.
Abstract. Permanent isolated proximal renal tubular acidosis (pRTA) with ocular abnormalities is a systemic disease involving short stature, isolated pRTA, mental retardation, and ocular abnormalities. Kidney Na + /HCO 3 - cotransporter (kNBC1) cDNA from peripheral lymphocytes from a patient with permanent isolated pRTA and bilateral glaucoma was screened, and a novel homozygous mutation, namely a cytosine-to-thymine transition at nucleotide 234, which resulted in the formation of a stop codon at codon 29, was identified. This homozygous mutation, Q29X, was identified in the unique 5′-end of the kNBC1 gene ( SLC4A4 ) of the patient. Cosegregation of this Q29X mutation with the disease and heterozygosity in the parents of the affected patient were observed. The absence of this mutation in 156 alleles from 78 Japanese individuals indicates that this mutation is directly related to the disease and is not a common DNA sequence polymorphism. This nonsense mutation predicts a truncated kNBC1 protein that lacks the 1007 amino acids of the carboxyl-terminus, and the effect on kNBC1 cotransport activity is likely to be a loss of function. In contrast, the pancreatic Na + /HCO 3 - cotransporter of the patient is not likely to be affected by this nonsense mutation. These results have implications for understanding the role of kNBC1 in the pathophysiologic processes of pRTA associated with ocular abnormalities and mental retardation.
Abstract Introduction/Aims Duchenne muscular dystrophy (DMD) presents with skeletal muscle weakness, followed by respiratory and cardiac muscle involvement. Recently, with the development of treatments, the need for a natural history to serve as a control for determining treatment efficacy in clinical trials has increased dramatically, however, few large-scale studies have investigated changes in these symptoms. The present study examined the natural history of Japanese DMD patients as a whole and individual patient with genetic mutations eligible for exon skipping therapy. Methods Medical records of 337 patients with DMD who visited Kobe University Hospital over a period of 30 years from their first visit until 20 years of age were examined. Results Serum creatine kinase levels showed a stair-step pattern of decline, with extremely high values until 6 and a rapid decline from 7 to 12 years of age. Both the median 10-meter run/walk velocity and rise-from-floor velocity peaked at the age of 4 years and declined with age. The values for respiratory function declined from the age of 11 years. The median left ventricular ejection fraction was >60% until the age of 12 years and rapidly declined from 13 to 15 years of age. Examination of the relationship between gene mutations eligible for exon-skipping therapy and natural history revealed no characteristic findings. Discussion We found that creatine kinase levels and motor, respiratory, and cardiac functions each exhibited unique changes over time. These findings will be useful in developing new therapeutic agents for DMD and in determining their efficacy in clinical trials.
Glucokinase-maturity-onset diabetes of the young (GCK-MODY; also known as MODY2) is a benign hyperglycemic condition, which generally does not require medical interventions. The only known exception is increased birthweight and related perinatal complications in unaffected offspring of affected women. As previous data were obtained mostly from white Europeans, the present study analyzed the pregnancy outcomes of Japanese women with GCK-MODY to better formulate the management plan for this population.The study participants were 34 GCK-MODY families whose members were diagnosed at Osaka City General Hospital during 2010-2017. A total of 53 pregnancies (40 from 23 affected women, 13 from 11 unaffected women) were retrospectively analyzed by chart review.Birthweights of unaffected offspring born to affected women were significantly greater as compared with those of affected offspring (P = 0.003). The risk of >4,000 g birthweight (16%), however, was lower as compared with that previously reported for white Europeans, and none of the offspring had complications related to large birthweight. Insulin treatment of the affected women resulted in a significant reduction in the birthweights of unaffected offspring. Perinatal complications including small-for-gestational age birthweight were found only in affected offspring born to insulin-treated women.In Japanese GCK-MODY families, unaffected offspring born to affected women were heavier than affected offspring. However, insulin treatment of affected women might not be advisable because of the lower risk of macrosomic birth injury, and an increased risk of perinatal complications in affected offspring.
X-linked adrenoleukodystrophy (ALD) is characterised by progressive multifocal demyelination of central nervous system and adrenocortical insufficiency. This disorder has been also associated with mutations in the ALD gene, encoding an ATP-binding transporter which is located in the peroxisomal membrane. Defect of the gene may lead to impaired peroxisomal beta-oxidation and increase of serum and tissue very long chain fatty acids (VLCFAs). Here we report the results of analysis of the ALD gene in a Japanese patient with childhood cerebral ALD. In our patient, by sequencing of the ALD cDNA, an 8 bp insertion (ACCCCCAG) was detected at the start of exon 9, which corresponded to nucleotides from position -1 to -8 of the 3' splice acceptor site of intron 8. Sequencing of genomic DNA showed a single nucleotide substitution at position-10 of the 3' splice acceptor site of intron 8 replacing a G with an A which activated a cryptic splice acceptor site. It is concluded that a splicing error was induced by a point mutation that created a novel splice acceptor site. This insertion created a nonsense codon downstream, producing a truncated ALD protein. His mother and younger sister with increased VLCFA ratios were heterozygotes of normal and mutant ALD genes.
Duchenne/Becker muscular dystrophies (DMD/BMD) are the most common inherited muscular disease and caused by mutations in the dystrophin gene. A half to two-thirds of DMD and BMD patients carry deletions (usually of several kilobases of genomic DNA). The clinical progression in DMD and BMD patients with deletions can be predicted in 92% of cases based on whether the deletion maintains or disrupts the translational reading frame (frame-shift hypothesis). However, some exceptional cases have been reported in which some posttranscriptional modifications were suggested, such as alternative splicing and reinitiation of translation. Splicing mutation is one kind of mutations of dystrophin gene, and usually induced by a small mutation of exon-intron boundary sequence. However, intraexonal small mutation also induces exon skipping, due to disruption of an exon recognition sequence, which is an intraexonal sequence and necessary for splicing of the upstream intron. Carrier diagnosis is one of the important clinical application of genetic diagnosis. In the case of DMD/BMD with deletions of the dystrophin gene, carrier diagnosis is difficult because of the existence of normal X chromosome. In these cases a linkage analysis is useful, and in some cases non-carriers can be directly diagnosed on the basis of microsattelite polymorphism detected in deleted region of patient. For the molecular diagnosis of DMD/BMD it is important to analyze not only at the genomic DNA level, but also at the mRNA, protein, and clinical levels. And the relationship between the molecular abnormality and clinical phenotype should be examined, especially extramuscular symptoms such as heart failure and mental retardation.
