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Background Oxidation Resistance 1 ( OXR1 ) gene is a highly conserved gene of the TLDc domain-containing family. OXR1 is involved in fundamental biological and cellular processes, including DNA damage response, antioxidant pathways, cell cycle, neuronal protection, and arginine methylation. In 2019, five patients from three families carrying four biallelic loss-of-function variants in OXR1 were reported to be associated with cerebellar atrophy. However, the impact of OXR1 on cellular functions and molecular mechanisms in the human brain is largely unknown. Notably, no human disease models are available to explore the pathological impact of OXR1 deficiency. Results We report a novel loss-of-function mutation in the TLDc domain of the human OXR1 gene, resulting in early-onset epilepsy, developmental delay, cognitive disabilities, and cerebellar atrophy. Patient lymphoblasts show impaired cell survival, proliferation, and hypersensitivity to oxidative stress. These phenotypes are rescued by TLDc domain replacement. We generate patient-derived induced pluripotent stem cells (iPSCs) revealing impaired neural differentiation along with dysregulation of genes essential for neurodevelopment. We identify that OXR1 influences histone arginine methylation by activating protein arginine methyltransferases (PRMTs), suggesting OXR1-dependent mechanisms regulating gene expression during neurodevelopment. We model the function of OXR1 in early human brain development using patient-derived brain organoids revealing that OXR1 contributes to the spatial–temporal regulation of histone arginine methylation in specific brain regions. Conclusions This study provides new insights into pathological features and molecular underpinnings associated with OXR1 deficiency in patients.

ObjectiveTo identify the genetic basis of a childhood-onset syndrome of variable severity characterised by progressive spinocerebellar ataxia, mental retardation, psychotic episodes and cerebellar atrophy.MethodsIdentification of the underlying mutations by whole exome and whole genome sequencing. Consequences were examined in patients’ cells and in yeast.ResultsTwo brothers from a consanguineous Palestinian family presented with progressive spinocerebellar ataxia, mental retardation and psychotic episodes. Serial brain imaging showed severe progressive cerebellar atrophy. Whole exome sequencing revealed a novel mutation: pitrilysin metallopeptidase 1 (PITRM1) c.2795C>T, p.T931M, homozygous in the affected children and resulting in 95% reduction in PITRM1 protein. Whole genome sequencing revealed a chromosome X structural rearrangement that also segregated with the disease. Independently, two siblings from a second Palestinian family presented with similar, somewhat milder symptoms and the same PITRM1 mutation on a shared haplotype. PITRM1T931M carrier frequency was 0.027 (3/110) in the village of the first family evaluated, and 0/300 among Palestinians from other locales. PITRM1 is a mitochondrial matrix enzyme that degrades 10–65 amino acid oligopeptides, including the mitochondrial fraction of amyloid-beta peptide. Analysis of peptide cleavage activity by the PITRM1T931M protein revealed a significant decrease in the degradation capacity specifically of peptides ≥40 amino acids.Conclusion PITRM1T931M results in childhood-onset recessive cerebellar pathology. Severity of PITRM1-related disease may be affected by the degree of impairment in cleavage of mitochondrial long peptides. Disruption and deletion of X linked regulatory segments may also contribute to severity.

Background Phelan–McDermid syndrome (PMS) is a neurodevelopmental disorder, caused by haploinsufficiency of the SHANK3 gene. In addition to global developmental delay (GDD)/intellectual disability (ID) and autism spectrum disorder (ASD), PMS is characterized by multiple neurologic, behavioral and multisystemic manifestations. Methods We aimed to establish a database of individuals with PMS in Israel. All participants underwent a detailed evaluation at a single medical center, and demographic, clinical, and genetic data were collected. Results Seventeen unrelated individuals with PMS (mean age 10 ± 8.2 years; range, 2.5–36 years) were enrolled (10 females, 59%), all of Jewish descent. Twelve cases (70%) were caused by deletions in chromosomal region 22q13.3, including mosaicism, ring chromosome and unbalanced translocation. The other 5 (30%) cases were due to single nucleotide variants (SNVs), while the de novo SNV c.3904dup (p.Ala1302GlyfsTer69), recurred in 3 cases. All 17 participants had GDD/ID (which was severe in 10, 59%), and ASD and seizures were present in 12 (70%) and 8 (47%) individuals, respectively. Additional frequent manifestations were sleep difficulties in 13 individuals (76%), bowel movement disorders in 13 (76%), urinary track involvement in 8 (47%) and endocrine disorders in 6 (35%). Abnormal but nonspecific findings on prenatal ultrasonography were noted in 3 participants (18%). The most common perinatal complication was prolonged jaundice in 5 infants (29%). Different medical treatment modalities, including cannabidiol (CBD) full-spectrum oil extracts, were used to ease symptoms, with variable results. Conclusions Our experience adds to current knowledge about clinical manifestations and potential symptomatic treatment of PMS in Israel. These findings may promote clinical research and serve as infrastructure for future clinical trials.

Cytochrome-c-oxidase (COX) subunit 4 (COX4) plays important roles in the function, assembly and regulation of COX (mitochondrial respiratory complex 4), the terminal electron acceptor of the oxidative phosphorylation (OXPHOS) system. The principal COX4 isoform, COX4-1, is expressed in all tissues, whereas COX4-2 is mainly expressed in the lungs, or under hypoxia and other stress conditions. We have previously described a patient with a COX4-1 defect with a relatively mild presentation compared to other primary COX deficiencies, and hypothesized that this could be the result of a compensatory upregulation of COX4-2. To this end, COX4-1 was downregulated by shRNAs in human foreskin fibroblasts (HFF) and compared to the patient’s cells. COX4-1, COX4-2 and HIF-1α were detected by immunocytochemistry. The mRNA transcripts of both COX4 isoforms and HIF-1 target genes were quantified by RT-qPCR. COX activity and OXPHOS function were measured by enzymatic and oxygen consumption assays, respectively. Pathways were analyzed by CEL-Seq2 and by RT-qPCR. We demonstrated elevated COX4-2 levels in the COX4-1-deficient cells, with a concomitant HIF-1α stabilization, nuclear localization and upregulation of the hypoxia and glycolysis pathways. We suggest that COX4-2 and HIF-1α are upregulated also in normoxia as a compensatory mechanism in COX4-1 deficiency.

Background Celiac disease (CD) is a complex autoimmune disorder that can lead to an inflammatory small intestinal villous atrophy and malabsorption. Hartnup disease is an autosomal recessive disorder caused by increased urinary excretion of neutral amino acids. Co-occurrence of Hartnup disease and CD is extremely rare with only a single case reported. Case presentation We report a 3-year girl with chronic diarrhea, Hypoalbuminemia and exfoliative erythema. She was diagnosed with celiac disease, which did not improve on gluten free diet. Hartnup disease was suspected and was confirmed by neutral aminoaciduria. Niacin was started and followed by dramatic improvement. Conclusion Presence of Celiac and Hartnup disease in single individual is very rare. Complete nutritional assessment of refractory celiac patient can reveal underlying nutritional deficiency.

Ethylmalonic encephalopathy (EE) is a rare autosomal recessive disorder caused by mutations in the ETHE1 gene and characterized by chronic diarrhea, encephalopathy, relapsing petechiae and acrocyanosis. Nephrotic syndrome has been described in an infant with EE but the renal histology findings were not described in previous reports. We report a Palestinian girl with EE who presented with chronic diarrhea, encephalopathy, petechial rash and acrocyanosis. Subsequently, she developed progressive deterioration of renal function caused by rapidly progressive glomerulonephritis resulting in death within few days. This is, to our knowledge, the first reported occurrence of rapidly progressive glomerulonephritis in a child with ethylmalonic encephalopathy. Its presence is a serious complication associated with poor prognosis and may be explained by the diffuse vascular damage

BackgroundThe LSM1 gene encodes a subunit of the conserved LSM1-7 protein complex involved in messenger RNA (mRNA) metabolism. Variants in the LSM1 gene have been described in two separate case reports. The first published report identified the homozygous splice-site variant c.231+4A>C, while the second reported a homozygous missense variant. Nevertheless, variation in LSM1 has yet to be established as disease-causing in humans.MethodsThrough exome sequencing and detailed phenotyping, we report six syndromic paediatric patients with the homozygous c.231+4A>C variant in the LSM1 gene, collected via GeneMatcher. GestaltMatcher was used to analyse facial feature similarity, and real-time quantitative PCR (RT-qPCR) confirmed the splice defect caused by the variant. Haplotype analysis assessed whether this variant resulted from independent occurrences or a common ancestral haplotype.ResultsPatients presented with dysmorphic facial features, developmental delay and multisystemic involvement, including urological, cardiac and skeletal manifestations, showcasing the phenotypic spectrum of this syndrome. RT-qPCR confirmed that the c.231+4A>C variant causes exon 3 skipping, producing negligible wild-type LSM1 mRNA expression. Elevated mutant isoform expression confirmed pathogenicity according to the American College of Medical Genetics and Genomics (ACMG) guidelines. We identified this variant in the Muslim Arab and Ashkenazi Jewish populations and determined that it represents a hotspot variant through haplotype analysis.ConclusionOur findings establish LSM1, and specifically the c.231+4A>C homozygous variant, as causative for a novel autosomal recessive syndromic neurodevelopmental disorder. These results expand the understanding of LSM1-related diseases and provide a foundation for further investigation of its molecular mechanisms.

We studied three newly diagnosed xeroderma pigmentosum complementation group G patients with markedly different clinical features. An Israeli-Palestinian girl (XP96TA) had severe abnormalities suggestive of the xeroderma pigmentosum/Cockayne syndrome complex including sun sensitivity, neurologic and developmental impairment, and death by age 6 y. A Caucasian girl (XP82DC) also had severe sun sensitivity with neurologic and developmental impairment and died at 5.8 y. In contrast, a mildly affected 14-y-old Caucasian female (XP65BE) had sun sensitivity but no neurologic abnormalities. XP96TA, XP82DC, and XP65BE fibroblasts showed marked reductions in post-ultraviolet cell survival and DNA repair but these were higher in XP65BE than in XP82DC. XP96TA fibroblasts had very low XPG mRNA expression levels whereas XP65BE fibroblasts had nearly normal levels. Host cell reactivation of an ultraviolet-treated reporter assigned all three fibroblast strains to the rare xeroderma pigmentosum complementation group G (only 10 other patients previously reported). XP96TA and XP82DC cells had mutations in both XPG alleles that are predicted to result in severely truncated proteins including stop codons and two base frameshifts. The mild XP65BE patient had an early stop codon mutation in the paternal allele. The XP65BE maternal allele had a single base missense mutation (G2817A, Ala874Thr) that showed residual ability to complement xeroderma pigmentosum complementation group G cells. These observations agree with earlier studies demonstrating that XPG mutations, which are predicted to lead to severely truncated proteins in both alleles, were associated with severe xeroderma pigmentosum/Cockayne syndrome neurologic symptoms. Retaining residual functional activity in one allele was associated with mild clinical features without neurologic abnormalities.

BackgroundOf our 1400 exome-studied patients, 67% originate from consanguineous families. ∼80% suffer from variable degree of intellectual disability (ID). The search for disease causing genes using homozygosity mapping was progressing slowly until 2010, then markedly accelerated by the introduction of exome analysis.ObjectivesTo identify the disease causing mutation(s) in three patients from two unrelated families who suffered from global developmental delay, severe ID and drug-responsive seizure disorder.MethodsExome analysis was performed in DNA of the three patients. The identified PIGC variants were generated and transfected into PIGC-defective mouse cells and the restoration of the surface expression of mouse CD90, CD48 and FLAER was assessed using flow cytometry. The expression of these proteins was also studied on the surface of patients' leucocytes.ResultsThree PIGC mutations were identified; homozygous p.L189W in one family and compound heterozygosity for p.L212P/p.R21X variants in another. PIGC participates in the biosynthesis of the glycosylphosphatidylinositol (GPI) anchor which tethers proteins to plasma membrane. In cells lacking PIGC protein, which were transfected with each of the PIGC variants, we detected a clear reduction of surface expression of GPI-anchored proteins. Furthermore, analyses of patients' leucocytes showed significant and constant decrease of CD16 surface expression in granulocytes, and moderate decrease of CD14, CD55, CD59 and FLAER levels.ConclusionsPIGC joins the list of genes in which mutations result in defective biosynthesis of GPI anchoring, manifesting by global developmental delay and seizure disorder. The lack of specific biomarker dictates exome sequencing as the diagnostic procedure of choice in similar patients.

In response to Ravera et al. “Fanconi anemia: from DNA repair to metabolism” commenting on our recent publication by Abu-Libdeh, Douiev et al., describing a pathogenic variant in the COX 4I1 gene simulating Fanconi anemia, we wish to add supplementary, pertinent information linking cytochrome c oxidase (COX, mitochondrial respiratory chain complex IV) dysfunction to oxidative stress and nuclear DNA damage. Elevated production of reactive oxygen species (ROS) in COX 4I1 deficient fibroblasts was detected in cells grown in glucose free medium and normalized by ascorbate or N-acetylcysteine supplementation. A pilot study shows positive nuclear staining with antibodies against Phospho-Histone H2A.X (Ser 139) indicating double-stranded DNA breaks (DBSs) both in COX 4I1 and in COX6B1 deficient fibroblasts. Additional investigation is required, and ongoing, to elucidate the precise mechanism of DNA damage in mitochondrial respiratory chain dysfunction and how it could be prevented.