Missense Research Articles

Aberrant N-glycosylation is a therapeutic target in carriers of a common and highly pleiotropic mutation in the manganese transporter ZIP8.

The treatment of defective glycosylation in clinical practice has been limited to patients with rare and severe phenotypes associated with congenital disorders of glycosylation (CDG). Carried by approximately 5% of the human population, the discovery of the highly pleiotropic, missense mutation in a manganese transporter ZIP8 has exposed under-appreciated roles for Mn homeostasis and aberrant Mn-dependent glycosyltransferases activity leading to defective N-glycosylation in complex human diseases. Here, we test the hypothesis that aberrant N-glycosylation contributes to disease pathogenesis of ZIP8 A391T-associated Crohn's disease. Analysis of N-glycan branching in intestinal biopsies demonstrates perturbation in active Crohn's disease and a genotype-dependent effect characterized by increased truncated N-glycans. A mouse model of ZIP8 391-Thr recapitulates the intestinal glycophenotype of patients carrying mutations in ZIP8. Borrowing from therapeutic strategies employed in the treatment of patients with CDGs, oral monosaccharide therapy with N-acetylglucosamine ameliorates the epithelial N-glycan defect, bile acid dyshomeostasis, intestinal permeability, and susceptibility to chemical-induced colitis in a mouse model of ZIP8 391-Thr. Together, these data support ZIP8 391-Thr alters N-glycosylation to contribute to disease pathogenesis, challenging the clinical paradigm that CDGs are limited to patients with rare diseases. Critically, the defect in glycosylation can be targeted with monosaccharide supplementation, providing an opportunity for genotype-driven, personalized medicine.

The anti-tumor effect of trifluridine via induction of aberrant mitosis is unaffected by mutations modulating p53 activity

The fluorinated thymidine analog trifluridine (FTD) is a chemotherapeutic drug commonly used to treat cancer; however, the mechanism by which FTD induces cytotoxicity is not fully understood. In addition, the effect of gain-of-function (GOF) missense mutations of the TP53 gene (encoding p53), which promote cancer progression and chemotherapeutic drug resistance, on the chemotherapeutic efficacy of FTD is unclear. Here, we revealed the mechanisms by which FTD-induced aberrant mitosis and contributed to cytotoxicity in both p53-null and p53-GOF missense mutant cells. In p53-null mutant cells, FTD-induced DNA double-stranded breaks, single-stranded DNA accumulation, and the associated DNA damage responses during the G2 phase. Nevertheless, FTD-induced DNA damage and the related responses were not sufficient to trigger strict G2/M checkpoint arrest. Thus, these features were carried over into mitosis, resulting in chromosome breaks and bridges, and subsequent cytokinesis failure. Improper mitotic exit eventually led to cell apoptosis, caused by the accumulation of extensive DNA damage and the presence of micronuclei encapsulated in the disrupted nuclear envelope. Upon FTD treatment, the behavior of the p53-GOF-missense mutant, isogenic cell lines, generated by CRISPR/Cas9 genome editing, was similar to that of p53-null mutant cells. Thus, our data suggest that FTD treatment overrode the effect on gene expression induced by p53-GOF mutants and exerted its anti-tumor activity in a manner that was independent of the p53 function.

Integrated Clinical Genotype-phenotype Characteristics of STAT3-mutated Myeloid Neoplasms.

STAT3 is a key transcription factor that mediates cancer progression through phosphorylation or gain-of-function mutations. STAT3 activation in myeloid neoplasms (MNs) is primarily mediated through phosphorylation. STAT3 mutation has only rarely been reported in MNs. We assessed the clinicopathologic and molecular genetic features of 32 STAT3-mutated MNs. The frequency of STAT3 mutation in MNs was <0.5%. Twenty (62.5%) cases were classified as acute myeloid leukemia (AML), 7 (21.9%) as myelodysplastic syndrome (MDS), 5 (15.6%) as chronic myelomonocytic leukemia (CMML), but none as myeloproliferative neoplasms (MPN). STAT3 mutations occurred at initial diagnosis in 22 (88%) cases, or at relapse or upon leukemic transformation. Clonal hierarchy analysis revealed that STAT3 mutations represented the dominant clone in 30% of AML cases, but were subclonal in MDS and CMML. Most were missense mutations located at the SH2 domain, Y640F being the most common. STAT3 mutation was accompanied by co-existing mutations in all cases, most frequently SRSF2, TET2, ASXL1, and SETBP1. STAT3 mutations were usually associated with morphologic dysplasia, increased blasts, and monosomy 7/del7q. With a median follow-up of 24.5 months, 21 patients died, 6 had persistent disease, and 5 achieved complete remission after stem cell transplantation. STAT3 mutation is present in various MNs, but not in MPN. It is often an early event or occurs upon leukemic transformation, suggesting an important role in the pathogenesis and progression of MNs by activating JAK-STAT pathway. It may help identify a subset of patients with MNs who may benefit from targeted therapy.

Cerebral Microvascular Density, Permeability of the Blood-Brain Barrier, and Neuroinflammatory Responses Indicate Early Aging Characteristics in a Marfan Syndrome Mouse Model.

Marfan Syndrome (MFS) is a connective tissue disorder due to mutations in fibrillin-1 ( Fbn1 ), where a Fbn1 missense mutation ( Fbn1 C1039G/+ ) can result in systemic increases in the bioavailability and signaling of transforming growth factor-β (TGF-β). In a well-established mouse model of MFS ( Fbn1 C1041G/+ ), pre-mature aging of the aortic wall and the progression of aortic root aneurysm are observed by 6-months-of-age. TGF-β signaling has been implicated in cerebrovascular dysfunction, loss of blood-brain barrier (BBB) integrity, and age-related neuroinflammation. We have reported that pre-mature vascular aging in MFS mice could extend to cerebrovasculature, where peak blood flow velocity in the posterior cerebral artery (PCA) of 6-month-old (6M) MFS mice was reduced, similarly to 12-month-old (12M) control mice. Case studies of MFS patients have documented neurovascular manifestations, including intracranial aneurysms, stroke, arterial tortuosity, as well as headaches and migraines, with reported incidence of pain and chronic fatigue. Despite these significant clinical observations, investigation into cerebrovascular dysfunction and neuropathology in MFS remains limited. Using 6M-control ( C57BL/6 ) and 6M-MFS ( Fbn1 C1041G/+ ) and healthy 12M-control male and female mice, we test the hypothesis that abnormal Fbn1 protein expression is associated with altered cerebral microvascular density, BBB permeability, and neuroinflammation in the PCA-perfused hippocampus, all indicative of a pre-mature aging brain phenotype. Using Glut1 staining, 6M-MFS mice and 12M-CTRL similarly present decreased microvascular density in the dentate gyrus (DG), cornu ammonis 1 (CA1), and cornu ammonis 3 (CA3) regions of the hippocampus. 6M-MFS mice exhibit increased BBB permeability in the DG, CA1, and CA3 as evident by Immunoglobulin G (IgG) staining, which was more comparable to 12M-CTRL mice. 6M-MFS mice show a higher number of microglia in the hippocampus compared to age-matched control mice, a pattern resembling that of 12M-CTRL mice. This study represents the first known investigation into neuropathology in a mouse model of MFS and indicates that the pathophysiology underlying MFS leads to a systemic pre-mature aging phenotype. This study is crucial for identifying and understanding MFS-associated neurovascular and neurological abnormalities, underscoring the need for research aimed at improving the quality of life and managing pre-mature aging symptoms in MFS and related connective tissue disorders.

Identification of a pathogenic mutation in ARPP21 in patients with amyotrophic lateral sclerosis

Background and objectiveBetween 5% and 10% of amyotrophic lateral sclerosis (ALS) cases have a family history of the disease, 30% of which do not have an identifiable underlying genetic cause...

Requirement of β subunit for the reduced voltage-gated Na+ current of a Brugada syndrome patient having novel double missense mutation (p.A385T/R504T) of SCN5A.

Mutations within the SCN5A gene, which encodes the α-subunit 5 (NaV1.5) of the voltage-gated Na+ channel, have been linked to three distinct cardiac arrhythmia disorders: long QT syndrome type 3, Brugada syndrome (BrS), and cardiac conduction disorder. In this study, we have identified novel missense mutations (p.A385T/R504T) within SCN5A in a patient exhibiting overlap arrhythmia phenotypes. This study aims to elucidate the functional consequences of SCN5A mutants (p.A385T/R504T) to understand the clinical phenotypes. Whole-cell patch-clamp technique was used to analyze the NaV1.5 current (INa) in HEK293 cells transfected with the wild-type and mutant SCN5A with or without SCN1B co-expression. The amplitude of INa was not altered in mutant SCN5A (p.A385T/R504T) alone. Furthermore, a rightward shift of the voltage-dependent inactivation and faster recovery from inactivation was observed, suggesting a gain-of-function state. Intriguingly, the coexpression of SCN1B with p.A385T/R504T revealed significant reduction of INa and slower recovery from inactivation, consistent with the loss-of-function in Na+ channels. The SCN1B dependent reduction of INa was also observed in a single mutation p.R504T, but p.A385T co-expressed with SCN1B showed no reduction. In contrast, the slower recovery from inactivation with SCN1B was observed in A385T while not in R504T. The expression of SCN1B is indispensable for the electrophysiological phenotype of BrS with the novel double mutations; p.A385T and p.R504T contributed to the slower recovery from inactivation and reduced current density of NaV1.5, respectively.

Transmembrane protein 53 craniotubular dysplasia (OMIM # 619727): The skeletal disease and consequent blindness of this new disorder

Craniotubular dysplasia, Ikegawa type (OMIM #619727) denotes the autosomal recessive skeletal disease identified in 2021 featuring blindness acquired in childhood. Five young members of four Indian families harbored a homozygous indel within TMEM53 (OMIM *619722), the gene that encodes transmembrane protein 53 (TMEM53). When intact, TMEM53 spans the nuclear envelope of osteoprogenitor cells, dampens BMP-SMAD signaling, and thereby slows bone formation. Consequently, defective TMEM53 accelerates osteogenesis. Herein, an American boy is compound heterozygous for a novel deletion and a novel missense mutation within TMEM53. His vision and sensorineural hearing became impaired. Radiographic survey revealed diploic thickening of his skull, broad calvarial and facial bones, skeletal modeling errors, vertebral body flattening, wide ribs, and osteopenia of expanded bones. DXA areal bone density (gm/cm2) Z-scores were low. His optic, auditory, and spinal canals were narrow. Mineral metabolism was intact. Serum alkaline phosphatase and osteocalcin levels were normal yet CTX was high. Iliac crest histomorphometry documented accelerated bone formation. His acute vision loss briefly improved following prednisone administration, optic canal decompression, and optic nerve sheath fenestration, but then progressed despite further surgeries and zoledronate treatment aimed to suppress bone turnover. Next generation sequencing of genes associated with elevated skeletal mass, including from high bone turnover, did not suggest an etiology. Whole genome sequencing then revealed within TMEM53: i) a paternally transmitted 54-base deletion, which included the mRNA splice acceptor site for exon 2 as well as 31 bases of exonic sequence (c. 62-23_92del), and ii) a maternally transmitted missense variant (c.650C > T, p.Ser217Leu: NM_024587.4/NP_078863.2) which is extremely rare in gnomAD (frequency = 0.000036), replaces Ser217 highly conserved across species, and is scored as damaging by SIFT and Mutation Taster. We call this new osteopathy TMEM53 craniotubular dysplasia.

Hereditary coagulation factor VII deficiency caused by novel compound heterozygous mutations c.572-1G>A and c.1037A>C in a Chinese pedigree

Hereditary coagulation factor VII (FVII) deficiency is a rare autosomal recessive bleeding disorder. The aims of this study were to identify and verify the pathogenic mutation sites in a family with hereditary coagulation FVII deficiency, and preliminarily explore the underlying mechanisms. We identified a novel combination of compound heterozygous mutations, c.572-1G>A and c.1037A>C in F7 gene, associated with FVII deficiency. The splice site mutation c.572-1G>A led to a truncation, resulting in the loss of the essential catalytic domain of the FVII protein. The c.1037A>C missense mutation has not been previously reported. Our study revealed that this mutation leads to steric hindrance between residues, causing significant changes in the energy and structure of the FVII protein, ultimately affecting its function. These changes disrupt the normal function of the FVII protein, accelerating the development of inherited FVII deficiency. Moreover, the mRNA expression of the F7 gene and the protein expression of the FVII antigen (FVII: Ag) were significantly lower in the proband, as well as in the proband's parents, compared to the healthy control (P<0.05). Our findings not only elucidate the genetic underpinning of FVII deficiency in the family studied but also contribute a new mutation to the known disease spectrum, potentially assisting in future diagnostic and therapeutic approaches.

ArabidopsisPROTODERMAL FACTOR2 binds lysophosphatidylcholines and transcriptionally regulates phospholipid metabolism.

Plant homeodomain leucine zipper IV (HD-Zip IV) transcription factors (TFs) contain an evolutionarily conserved steroidogenic acute regulatory protein (StAR)-related lipid transfer (START) domain. While the START domain is required for TF activity, its presumed role as a lipid sensor is not clear. Here we used tandem affinity purification from Arabidopsis cell cultures to demonstrate that PROTODERMAL FACTOR2 (PDF2), a representative member that controls epidermal differentiation, recruits lysophosphatidylcholines (LysoPCs) in a START-dependent manner. Microscale thermophoresis assays confirmed that a missense mutation in a predicted ligand contact site reduces lysophospholipid binding. We additionally found that PDF2 acts as a transcriptional regulator of phospholipid- and phosphate (Pi) starvation-related genes and binds to a palindromic octamer with consensus to a Pi response element. Phospholipid homeostasis and elongation growth were altered in pdf2 mutants according to Pi availability. Cycloheximide chase experiments revealed a role for START in maintaining protein levels, and Pi starvation resulted in enhanced protein destabilization, suggesting a mechanism by which lipid binding controls TF activity. We propose that the START domain serves as a molecular sensor for membrane phospholipid status in the epidermis. Our data provide insights toward understanding how the lipid metabolome integrates Pi availability with gene expression.

Jasmonate-insensitive mutant jar1b prevents petal elongation and flower opening coupling with parthenocarpic fruit development in Cucurbita pepo

Jasmonates are growth regulators that play a key role in flower development, fruit ripening, root growth, and plant defence. The study explores the coordination of floral organ maturation to ensure proper flower opening for pollination and fertilization. A new mutant (jar1b) was discovered, lacking petal elongation and flower opening but showing normal pistil and stamen development, leading to parthenocarpic fruit development. The mutation also enhanced the elongation of roots while reducing the formation of root hairs. BSA sequencing showed that jar1b is a missense mutation in the gene CpJAR1B, which encodes the enzyme that catalyzes the conjugation between JA and the amino acid isoleucine. The loss of function mutation in CpJAR1B produced a deficiency in biologically active (+) -7-iso-jasmonoyl-L-isoleucine (JA-Ile), which was not complemented by the paralogous gene CpJAR1A or any other redundant gene. Exogenous application of methyl jasmonate (MeJA) demonstrated that jar1b is partially insensitive to JA in both flowers and roots. Further experimentation involving the combination of JA-Ile deficient and ethylene-deficient, and ET insensitive mutations in double mutants revealed that CpJAR1B mediated ET action in female petal maturation and flower opening, but JA and ET have independent additive effects as negative regulators of the set and development of squash fruits. CpJAR1B also regulated the aperture of male flowers in an ethylene-independent manner. The root phenotype of jar1b and effects of external MeJA treatments indicated that CpJAR1B has a dual role in root development, inhibiting the elongation of primary and secondary roots, but promoting the formation of root hairs.

Molecular and Clinical Features of Congenital Hypothyroidism Due to Multiple DUOX2 Variants.

Background: DUOX2 is one of the major causative genes of congenital hypothyroidism (CH). Still, the mutation spectrum and clinical outcomes of biallelic DUOX2 variants are not fully understood. This study aimed to elucidate the molecular features and long-term clinical manifestations of CH caused by multiple pathogenic DUOX2 variants. Methods: A total of 255 patients with CH were screened for rare variants of 11 known causative genes. DUOX2 variants were classified according to their protein structure and residual activity. In vitro assays were performed for several variants of unknown functions. Clinical analyses were conducted for patients with multiple pathogenic variants of DUOX2 but not of other genes. Results: We identified 24 pathogenic variants of DUOX2, together with two benign variants and seven variants of uncertain significance, in 63 patients. The pathogenic variants included three missense substitutions and one frameshift variant that have not yet been linked to CH. Twenty-one patients carried multiple pathogenic DUOX2 variants without any other pathogenic gene variants. Three of the 21 patients harbored homozygous variants. Family analysis, long-read amplicon sequencing, and haplotype phasing confirmed compound heterozygosity of the DUOX2 variants in 14 patients, whereas the allelic positions of the variants in the remaining four patients could not be determined. Of the 21 patients, 19 were treated with levothyroxine; their ages at drug withdrawal ranged from 9 months to 21.4 years. Three patients required retreatment after drug-free intervals of 6 months, 8 months, and 10 years. There were no differences in clinical severity among patients with DUOX2 amorphic/amorphic, amorphic/hypomorphic, and hypomorphic/hypomorphic variants. Conclusions: These results broaden the mutational spectrum of DUOX2. Furthermore, our data imply that patients with multiple pathogenic DUOX2 variants typically exhibit transient CH without significant genotype-phenotype correlations. Most importantly, this study demonstrated for the first time that these patients are at risk of developing recurrent hypothyroidism after a long drug-free interval.

Pathological mutations in the phospholamban cytoplasmic region affect its topology and dynamics modulating the extent of SERCA inhibition

Phospholamban (PLN) is a 52 amino acid regulin that allosterically modulates the activity of the sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) in the heart muscle. In its unphosphorylated form, PLN binds SERCA within its transmembrane (TM) domains, approximately 20 Å away from the Ca2+ binding site, reducing SERCA's apparent Ca2+ affinity (pKCa) and decreasing cardiac contractility. During the enzymatic cycle, the inhibitory TM domain of PLN remains anchored to SERCA, whereas its cytoplasmic region transiently binds the ATPase's headpiece. Phosphorylation of PLN at Ser16 by protein kinase A increases the affinity of its cytoplasmic domain to SERCA, weakening the TM interactions with the ATPase, reversing its inhibitory function, and augmenting muscle contractility. How the structural changes caused by pathological mutations in the PLN cytoplasmic region are transmitted to its inhibitory TM domain is still unclear. Using solid-state NMR spectroscopy and activity assays, we analyzed the structural and functional effects of a series of mutations and their phosphorylated forms located in the PLN cytoplasmic region and linked to dilated cardiomyopathy. We found that these missense mutations affect the overall topology and dynamics of PLN and ultimately modulate its inhibitory potency. Also, the changes in the TM tilt angle and cytoplasmic dynamics of PLN caused by these mutations correlate well with the extent of SERCA inhibition. Our study unveils new molecular determinants for designing variants of PLN that outcompete endogenous PLN to regulate SERCA in a tunable manner.

Select gene mutations associated with survival outcomes in ER-positive ERBB2-negative early-stage invasive breast cancer: A single-institutional tissue bank study.

The prognostic capability of targeted sequencing of primary tumors in patients with estrogen receptor-positive, human epidermal growth factor receptor-2-negative early-stage invasive breast cancer (EBC) in a real-world setting is uncertain. Therefore, we aimed to determine the correlation between a 22-gene mutational profile and long-term survival outcomes in patients with ER+/ERBB2- EBC. A total of 73 women diagnosed with ER+/ERBB2- EBC between January 10, 2004, and June 2, 2008, were followed up until December 31, 2022. Univariate and multivariate Cox models were constructed to plot the relapse-free survival (RFS) and overall survival (OS). The log-rank test derived p-value was obtained. For external validation, we performed a survival analysis of 1163 comparable patients retrieved from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) dataset. At follow-up, 16 (21.9%) patients had relapsed, while 21 (nearly 29%) harbored mutant genes. Thirty-three missense mutations were detected in 14 genes. The median ages were 51 and 46 years in patients with and without mutations, respectively. Patients with any mutation had a 1.85-fold higher risk of relapse (hazard ratio [HR]: 1.85, 95% confidence interval [CI]: 0.60-5.69) compared to those without any mutation. Patients who harbored any of the six genes (MAP2K4, FGFR3, APC, KIT, RB1, and PTEN) had a nearly 6-fold increase in the risk of relapse (HR: 5.82, 95% CI: 1.31-18.56; p = 0.0069). Multivariate Cox models revealed that the adjusted HR for RFS and OS were 6.67 (95% CI: 1.32-27.57) and 8.31 (p = 0.0443), respectively. METABRIC analysis also demonstrated a trend to significantly worse RFS (p = 0.0576) in the subcohort grouped by having a mutation in any of the six genes. Our single-institution tissue bank study of Taiwanese women with ER+/ERBB2- EBC suggests that a novel combination of six gene mutations might have prognostic capability for survival outcomes.

A force-sensitive mutation reveals a non-canonical role for dynein in anaphase progression.

The diverse roles of the dynein motor in shaping microtubule networks and cargo transport complicate in vivo analysis of its functions significantly. To address this issue, we have generated a series of missense mutations in Drosophila Dynein heavy chain. We show that mutations associated with human neurological disease cause a range of defects, including impaired cargo trafficking in neurons. We also describe a novel microtubule-binding domain mutation that specifically blocks the metaphase-anaphase transition during mitosis in the embryo. This effect is independent from dynein's canonical role in silencing the spindle assembly checkpoint. Optical trapping of purified dynein complexes reveals that this mutation only compromises motor performance under load, a finding rationalized by the results of all-atom molecular dynamics simulations. We propose that dynein has a novel function in anaphase progression that depends on it operating in a specific load regime. More broadly, our work illustrates how in vivo functions of motors can be dissected by manipulating their mechanical properties.

Wheat NAC transcription factor NAC5-1 is a positive regulator of senescence.

Wheat (Triticum aestivum L.) is an important source of both calories and protein in global diets, but there is a trade-off between grain yield and protein content. The timing of leaf senescence could mediate this trade-off as it is associated with both declines in photosynthesis and nitrogen remobilization from leaves to grain. NAC transcription factors play key roles in regulating senescence timing. In rice, OsNAC5 expression is correlated with increased protein content and upregulated in senescing leaves, but the role of the wheat ortholog in senescence had not been characterized. We verified that NAC5-1 is the ortholog of OsNAC5 and that it is expressed in senescing flag leaves in wheat. To characterize NAC5-1, we combined missense mutations in NAC5-A1 and NAC5-B1 from a TILLING mutant population and overexpressed NAC5-A1 in wheat. Mutation in NAC5-1 was associated with delayed onset of flag leaf senescence, while overexpression of NAC5-A1 was associated with slightly earlier onset of leaf senescence. DAP-seq was performed to locate transcription factor binding sites of NAC5-1. Analysis of DAP-seq and comparison with other studies identified putative downstream target genes of NAC5-1 which could be associated with senescence. This work showed that NAC5-1 is a positive transcriptional regulator of leaf senescence in wheat. Further research is needed to test the effect of NAC5-1 on yield and protein content in field trials, to assess the potential to exploit this senescence regulator to develop high-yielding wheat while maintaining grain protein content.

Coat colour in marsupials: genetic variants at the ASIP locus determine grey and black fur of the brushtail possum.

The possession of fur or hair is a defining characteristic of mammals and can occur in a variety of colours and patterns. While genetic determinants of coat colour are well described in eutherian 'placental' mammals, the other major mammalian infraclass, marsupials, is grossly understudied. The fur of the common brushtail possum (Trichosurus vulpecula), an iconic native mammal found throughout Australia and introduced into Aotearoa New Zealand, possesses two main colour morphs: grey and black. To identify genetic variants associated with coat colour, we performed a genome-wide association study (GWAS) with genotype by sequencing (GBS) data. Single nucleotide variants (SNVs) on chromosome 3, close to the agouti signalling protein (ASIP) gene that controls the temporal and spatial distribution of pigments in eutherian mammals, were identified. Fine-mapping identified a C>T variant at chr3:100483705 that results in a ASIP:p.Arg115Cys missense substitution, and animals homozygous for this variant have black fur. In addition to uncovering the first genetic determinant of coat colour in a natural marsupial population, comparative analysis of ASIP in divergent marsupial species identified the dasyurids as having accelerated evolution, reflecting their well described diversity of coat colour and pattern.

Molecular Analysis of OCA1 and OCA2 Genes in Sindhi Inbred Families

Purpose: The purpose of this study was to identify the common mutations of (Oculocutaneous albinism) OCA1 and OCA2 genes in Sindhi Inbred Families. Study Design: Descriptive cross-sectional study. Place and Duration of Study: Liaquat University of Medical and Health Sciences (LUMHS), Jamshoro, Pakistan, from October, 2020 to September, 2022. Methods: Forty-four patients of eight families with clinically diagnosed OCA and Ocular albinism (OA) with or without family history were recruited for this study and all affected individuals other than OCA were excluded from the study. A single missense substitution was identified in the OCA1 and OCA2 using PolyPhen 2, Mutation Taster and I-Mutant software. Results: Out of 8 randomly chosen OCA afflicted families, there were two carriers and two affected individuals identified in family III. In exon 4 of the OCA1 gene, a common mutation (homozygous) c.1255 G&gt;A (p.Gly419Arg) was identified. In three-generation pedigree for the albinism family VII was identified, including two affected, one carrier, and two normal people. Participants in this family who carried the 1045-15 T&gt;G mutation in the OCA2 gene were affected. Conclusion: Albinism affected individuals in Pakistan have varying phenotypic and genetic presentations. This is due to the fact that the population of Pakistan and those of Sindhi ancestry are heavily inbred, consanguineous, segregated, and afflicted by hereditary diseases.

A novel KIF11 missense mutation causing Microcephaly with or without chorioretinopathy, lymphedema, or mental retardation (MCLMR): A case report and literature review

A novel KIF11 missense mutation causing Microcephaly with or without chorioretinopathy, lymphedema, or mental retardation (MCLMR): A case report and literature review

Structure and function of the SIT1 proline transporter in complex with the COVID-19 receptor ACE2

Proline is widely known as the only proteogenic amino acid with a secondary amine. In addition to its crucial role in protein structure, the secondary amino acid modulates neurotransmission and regulates the kinetics of signaling proteins. To understand the structural basis of proline import, we solved the structure of the proline transporter SIT1 in complex with the COVID-19 viral receptor ACE2 by cryo-electron microscopy. The structure of pipecolate-bound SIT1 reveals the specific sequence requirements for proline transport in the SLC6 family and how this protein excludes amino acids with extended side chains. By comparing apo and substrate-bound SIT1 states, we also identify the structural changes that link substrate release and opening of the cytoplasmic gate and provide an explanation for how a missense mutation in the transporter causes iminoglycinuria.

Sporadic hemiplegic migraine with novel missense mutation in the SCN1A gene and positive response to anti-CGRP antibody: a case report

Sporadic hemiplegic migraine with novel missense mutation in the SCN1A gene and positive response to anti-CGRP antibody: a case report