Mechanism and regulation of cargo entry into the Commander endosomal recycling pathway.

Commander is a multiprotein complex that orchestrates endosomal recycling of integral cargo proteins and is essential for normal development. While the structure of this complex has recently been described, how cargo proteins are selected for Commander-mediated recycling remains unclear. Here we identify the mechanism through which the unstructured carboxy-terminal tail of the cargo adaptor sorting nexin-17 (SNX17) directly binds to the Retriever sub-complex of Commander.

Gain-of-function MYCN causes a megalencephaly-polydactyly syndrome manifesting mirror phenotypes of Feingold syndrome.

MYCN, a member of the MYC proto-oncogene family, regulates cell growth and proliferation. Somatic mutations of MYCN are identified in various tumors, and germline loss-of-function variants are responsible for Feingold syndrome, characterized by microcephaly. In contrast, one megalencephalic patient with a gain-of-function variant in MYCN, p.

Structure of the endosomal Commander complex linked to Ritscher-Schinzel syndrome.

The Commander complex is required for endosomal recycling of diverse transmembrane cargos and is mutated in Ritscher-Schinzel syndrome. It comprises two sub-assemblies: Retriever composed of VPS35L, VPS26C, and VPS29; and the CCC complex which contains twelve subunits: COMMD1-COMMD10 and the coiled-coil domain-containing (CCDC) proteins CCDC22 and CCDC93. Combining X-ray crystallography, electron cryomicroscopy, and in silico predictions, we have assembled a complete structural model of Commander.

Two children with hypophosphatasia with a heterozygous c.1559delT variant in the gene, the most common variant in Japanese populations.

Hypophosphatasia (HPP), a genetic disorder characterized by decreased tissue-nonspecific alkaline phosphatase (TNSALP) activity, is caused by loss-of-function mutations in the gene, which encodes TNSALP. The most frequent pathogenic variant in Japanese patients with HPP is a frameshift mutation in the gene, c.1559delT, and its carrier frequency is reported to be one in 480 in the Japanese population.

Clinical diversity and molecular mechanism of VPS35L-associated Ritscher-Schinzel syndrome.

Purpose: The Retriever subunit is the third responsible gene for Ritscher-Schinzel syndrome (RSS) after and . To date, only one pair of siblings have been reported and their condition was significantly more severe than typical RSS. This study aimed to understand the clinical spectrum and underlying molecular mechanism in VPS35L-associated RSS.

Germline variants in tumor suppressor FBXW7 lead to impaired ubiquitination and a neurodevelopmental syndrome.

Neurodevelopmental disorders are highly heterogenous conditions resulting from abnormalities of brain architecture and/or function. FBXW7 (F-box and WD-repeat-domain-containing 7), a recognized developmental regulator and tumor suppressor, has been shown to regulate cell-cycle progression and cell growth and survival by targeting substrates including CYCLIN E1/2 and NOTCH for degradation via the ubiquitin proteasome system. We used a genotype-first approach and global data-sharing platforms to identify 35 individuals harboring de novo and inherited FBXW7 germline monoallelic chromosomal deletions and nonsense, frameshift, splice-site, and missense variants associated with a neurodevelopmental syndrome.

Expanding the phenotypic spectrum of ARCN1-related syndrome.

Purpose: This study aimed to describe the phenotypic and molecular characteristics of ARCN1-related syndrome.

Methods: Patients with ARCN1 variants were identified, and clinician researchers were connected using GeneMatcher and physician referrals. Clinical histories were collected from each patient.

Digenic mutations in and impair formaldehyde clearance and cause a multisystem disorder, AMeD syndrome.

Rs671 in the aldehyde dehydrogenase 2 gene () is the cause of Asian alcohol flushing response after drinking. ALDH2 detoxifies endogenous aldehydes, which are the major source of DNA damage repaired by the Fanconi anemia pathway. Here, we show that the rs671 defective allele in combination with mutations in the alcohol dehydrogenase 5 gene, which encodes formaldehyde dehydrogenase ( ), causes a previously unidentified disorder, AMeD (aplastic anemia, mental retardation, and dwarfism) syndrome.

A novel missense variant in CUL3 shows altered binding ability to BTB-adaptor proteins leading to diverse phenotypes of CUL3-related disorders.

CUL3 forms Cullin-Ring ubiquitin ligases (CRL) with Ring-box protein and BTB-adaptor proteins. A variety of BTB-adaptor proteins have been reported to interact with the N-terminus of CUL3, which makes it possible to recognize various substrates for degradation. Regarding the association of CUL3 with neurodevelopmental disorders, a recent study reported three patients with global developmental delay, who carried de novo variants in CUL3.

Expanding the phenotype of biallelic loss-of-function variants in the NSUN2 gene: Description of four individuals with juvenile cataract, chronic nephritis, or brain anomaly as novel complications.

The NSUN2 gene encodes a tRNA cytosine methyltransferase that functions in the maturation of leucyl tRNA (Leu) (CAA) precursors, which is crucial for the anticodon-codon pairing and correct translation of mRNA. Biallelic loss of function variants in NSUN2 are known to cause moderate to severe intellectual disability. Microcephaly, postnatal growth retardation, and dysmorphic facial features are common complications in this genetic disorder, and delayed puberty is occasionally observed.

Phosphorylated proteome analysis of a novel germline ABL1 mutation causing an autosomal dominant syndrome with ventricular septal defect.

Background: A gain-of-function mutation in germline ABL1 causes a syndrome including congenital heart defects. However, the molecular mechanisms of this syndrome remain unknown. In this study, we found a novel ABL1 mutation in a Japanese family with ventricular septal defect, finger contracture, skin abnormalities and failure to thrive, and the molecular mechanisms of these phenotypes were investigated.

Two mouse models carrying truncating mutations in Magel2 show distinct phenotypes.

Schaaf-Yang syndrome (SYS) is a neurodevelopmental disorder caused by truncating variants in the paternal allele of MAGEL2, located in the Prader-Willi critical region, 15q11-q13. Although the phenotypes of SYS overlap those of Prader-Willi syndrome (PWS), including neonatal hypotonia, feeding problems, and developmental delay/intellectual disability, SYS patients show autism spectrum disorder and joint contractures, which are atypical phenotypes for PWS. Therefore, we hypothesized that the truncated Magel2 protein could potentially produce gain-of-function toxic effects.

Severe achondroplasia due to two de novo variants in the transmembrane domain of FGFR3 on the same allele: A case report.

Background: Achondroplasia (ACH), the most common form of short-limbed skeletal dysplasia, is caused by gain-of-function mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. More than 97% of patients result from a heterozygous p.G380R mutation in the FGFR3 gene.

Novel compound heterozygous MCOLN1 mutations identified in a Japanese girl with severe developmental delay and thin corpus callosum.

Mucolipidosis type IV (MLIV) is a rare lysosomal storage disorder causing severe psychomotor developmental delay and progressive visual impairment. MLIV is an autosomal recessive disease caused by mutations in MCOLN1, which encodes for mucolipin-1. Here, we report a case of a 4-year-old Japanese girl with severe intellectual disability and motor deficits.

Novel biallelic FA2H mutations in a Japanese boy with fatty acid hydroxylase-associated neurodegeneration.

FA2H encodes fatty acid 2-hydroxylase, which plays a significant role in maintaining the neuronal myelin sheath. Previous reports have revealed that a FA2H mutation leads to spastic paraplegia, leukodystrophy, and neurodegeneration with brain iron accumulation, collectively referred to as fatty acid hydroxylase-associated neurodegeneration (FAHN). The disease severity of FAHN varies among individual patients and may be explained by the enzyme activity of FA2H mutant proteins.

Biallelic VPS35L pathogenic variants cause 3C/Ritscher-Schinzel-like syndrome through dysfunction of retriever complex.

Background: 3C/Ritscher-Schinzel syndrome is characterised by congenital cranio-cerebello-cardiac dysplasia, where and are accepted as the causative genes. In combination with the retromer or retriever complex, these genes play a role in endosomal membrane protein recycling. We aimed to identify the gene abnormality responsible for the pathogenicity in siblings with a 3C/Ritscher-Schinzel-like syndrome, displaying cranio-cerebello-cardiac dysplasia, coloboma, microphthalmia, chondrodysplasia punctata and complicated skeletal malformation.

Constitutive activation of mTORC1 signaling induced by biallelic loss-of-function mutations in SZT2 underlies a discernible neurodevelopmental disease.

There have been increasing number of reports of SZT2-related neurological diseases, the main symptoms of which are epilepsy, developmental delay, macrocephaly and a dysmorphic corpus callosum. SZT2 functions as a regulator of mechanistic target of rapamycin complex 1 (mTORC1) signaling in cultured human cell lines and mouse tissues. However, it remains to be determined whether mutations in SZT2 in human patients alter mTORC1 signaling.

de novo gain-of-function mutation in a patient with a novel megalencephaly syndrome.

Background: In this study, we aimed to identify the gene abnormality responsible for pathogenicity in an individual with an undiagnosed neurodevelopmental disorder with megalencephaly, ventriculomegaly, hypoplastic corpus callosum, intellectual disability, polydactyly and neuroblastoma. We then explored the underlying molecular mechanism.

Methods: Trio-based, whole-exome sequencing was performed to identify disease-causing gene mutation.

Distinctive facies, macrocephaly, and developmental delay are signs of a PTEN mutation in childhood.

Background: Germline mutations of the PTEN gene are responsible for several PTEN hamartoma tumor syndromes. They are also implicated as a cause of macrocephaly and mild to severe developmental delay, regardless of the presence or absence of hamartomas in childhood. Nevertheless, because of limited information, the clinical features present during childhood in patients with a PTEN mutation are yet to be elucidated.

Disruption of atherosclerotic neointima seven years after bare metal stent deployment.

A 58-year-old male with a history of prior myocardial infarction, hypertension, and dyslipidemia was admitted due to deteriorating exertional angina. A bare metal stent (Multilink plus™, GUIDANT Corporation, Santa Clara, CA, USA) had been implanted into the proximal left anterior descending artery because of ST-elevation myocardial infarction 7 years earlier. Optical coherence tomography (OCT) showed a disruption of the atherosclerotic neointima overlying the stent.