TNNI1 Mutated in Autosomal Dominant Proximal Arthrogryposis

ObjectivesThe main objective of this case report is to identify a gene associated with a Japanese family with autosomal dominant arthrogryposis.MethodsWe performed clinicopathologic diagnosis and genomic analysis using trio-based exome sequencing.ResultsA 14-year-old boy had contractures in the proximal joints, and the serum creatine kinase level was elevated. Muscle biopsy demonstrated a moth-eaten appearance in some type 1 fibers, and electron microscopic analysis revealed that type 1 fibers had Z disk streaming. We identified a heterozygous nonsense variant, c.523A>T (p.K175*), in TNNI1 in the family.DiscussionThe altered amino acid residue is within the tropomyosin-binding site near the C-terminus, in a region homologous to the variational hotspot of Troponin I2 (TNNI2), which is associated with distal arthrogryposis type 1 and 2b. Compared with patients with TNNI2 variants, our patient had a milder phenotype and proximal arthrogryposis. We report here a case of proximal arthrogryposis associated with a TNNI1 nonsense variant, which expands the genetic and clinical spectrum of this disease. Further functional and genetic studies are required to clarify the role of TNNI1 in the disease.

Confirming Pathogenicity of the F386L PSEN1 Variant in a South Asian Family With Early-Onset Alzheimer Disease

ObjectivesThe F386L PSEN1 variant has been reported in 1 Japanese family with limited clinical information. We aimed to prove that F386L is pathogenic by demonstrating that it segregates with early-onset Alzheimer disease (AD).MethodsEight individuals in a South Asian family provided DNA for genetic testing and underwent a neurologic examination.ResultsThe female proband was diagnosed with AD at age 45 years and died at age 49 years. She had a CSF biomarker profile consistent with AD, and her florbetaben PET scan was amyloid positive with high uptake in the striatum. Her MRI showed no prominent white matter disease. Her affected relatives had an age at onset range of 38–57 years and had imaging and biomarker profiles similar to hers.DiscussionThe results presented here, in conjunction with the prior report, confirm the pathogenicity of F386L. Furthermore, our study highlights the importance of studying families from underrepresented populations to identify or confirm the pathogenicity of rare variants that may be specific to certain genetic ancestries.

8050 議題之考量—由社會轉變及傳統家庭結構分析—

<p>日本因進入快速老化的社會，故浮現年長者須面對的社會問題，同時，因社會及經濟系統的去穩定作用，例如嚴厲失業環境或學校或工作場合與他人的增強競爭，開始有人因沒有對社會生活的適應能力而窩居家中、隔絕於社會，這些人被稱為繭居族。當他們退出社會且窩在家中愈久，年紀漸增也失去獲得自撐所需要的技能，因而造成 80 餘歲的父母要用其退休金去支撐其 50 餘歲的孩子，此稱為 8050 議題。</p> <p>社福組織及研究者主要論辯點在於快速轉變的社會如何形成繭居族以及其行為如何影響 8050 議題，然而，因該論點聚焦於社會快速轉變，而缺乏傳統家庭結構與價值如何影響 8050 議題的可能性，日本的家庭似乎仍保留傳統習俗，而這些習俗仍影響著家庭的思維與行為。</p> <p>基於以上背景，本論文將結合快速社會轉變及傳統家庭結構與價值兩個面向之概念，以釐清 8050 議題之機轉。</p> <p>&nbsp;</p><p>Since Japan has entered into super aging society, there have appeared social problems with which elderly people have faced. Simultaneously, because of destabilization of society and economic system such as tough employment environments or intensifying competition with others in schools or working places, there were people who isolated from society and kept staying home for long time due to maladaptive response to social life. These people are called as hikikomori. As they withdrew from society and stayed their houses longer and longer, they got aged and lost the opportunity to acquire skills necessary for their self-support. As a consequence, parents in their 80s who are receiving pensions need to support their children in their 50s. This issue is called as the 8050 issue. Social service organizations and researchers mainly argue how drastic social transformation produce hikikomori and how their behaviours influence toughness of the 8050 issue. However, because of the focus on the influence by drastic social transformation, their arguments would lack the prospects about how traditional family structure and value influence the 8050 issue. Japanese family seems to remain traditional custom and such custom still affects family’s thoughts and behaviours. Due to these backgrounds, this paper will clarify the mechanism of 8050 issue with combining both of theories of drastic social transformation and concepts about traditional family structure and value.</p> <p>&nbsp;</p>

Family Policy Awareness and Marital Intentions: A National Survey Experimental Study

Despite extensively examining the effects of family policies on marriage and fertility rates, previous research has paid little attention to the process of policy implementation and has implicitly assumed that individuals are fully aware of the policy information when making marital and fertility decisions. Challenging this assumption, we theorize policy awareness as an important mechanism for understanding the potential influence of family policies on individuals' marital intentions, an understudied yet crucial determinant of family formation behavior. In an experiment using a national survey of young unmarried individuals in Japan, respondents were randomly assigned to treatment and control groups. The treatment group was informed about 17 Japanese family policy benefits, but most of the respondents knew none or only a few of these benefits. After exposure to the policy information, the treatment group had significantly higher marital intentions than the control group, which had similar baseline characteristics but no information exposure. Crucially, such positive effects were particularly pronounced among high-educated women and high- and low-educated men, reflecting the differentiated effects of policy awareness under Japan's traditional gender role norms. Overall, these findings highlight the pivotal role of policy awareness during the family formation process and contribute to the debate over whether and how family policies may influence different subpopulations.

First Japanese Family With PDX1-MODY (MODY4): A Novel PDX1 Frameshift Mutation, Clinical Characteristics, and Implications

Context The PDX1 gene encodes pancreatic and duodenal homeobox, a critical transcription factor for pancreatic β-cell differentiation and maintenance of mature β-cells. Heterozygous loss-of-function mutations cause PDX1-MODY (MODY4). Case Description Our patient is an 18-year-old lean man who developed diabetes at 16 years of age. Given his early-onset age and leanness, we performed genetic testing. Targeted next-generation sequencing and subsequent Sanger sequencing detected a novel heterozygous frameshift mutation (NM_00209.4:c.218delT. NP_000200.1: p.Leu73Profs*50) in the PDX1 transactivation domain that resulted in loss-of-function and was validated by an in vitro functional study. The proband and his 56-year-old father, who had the same mutation, both showed markedly reduced insulin and gastric inhibitory polypeptide (GIP) secretion compared with the dizygotic twin sister, who was negative for the mutation and had normal glucose tolerance. The proband responded well to sitagliptin, suggesting its utility as a treatment option. Notably, the proband and his father showed intriguing phenotypic differences: the proband had been lean for his entire life but developed early-onset diabetes requiring an antihyperglycemic agent. In contrast, his father was overweight, developed diabetes much later in life, and did not require medication, suggesting the oligogenic nature of PDX1-MODY. A review of all reported cases of PDX1-MODY also showed heterogeneous phenotypes regarding onset age, obesity, and treatment, even in the presence of the same mutation. Conclusions We identified the first Japanese family with PDX1-MODY. The similarities and differences found among the cases highlight the wide phenotypic spectrum of PDX1-MODY.