ABSTRACT
Recessive gene mutations underlie many developmental disorders and often lead to disabling neurological problems. Here, we report identification of a homozygous c.170G>A (p.Cys57Tyr or C57Y) mutation in the gene coding for protein disulfide isomerase A3 (PDIA3, also known as ERp57), an enzyme that catalyzes formation of disulfide bonds in the endoplasmic reticulum, to be associated with syndromic intellectual disability. Experiments in zebrafish embryos show that PDIA3C57Y expression is pathogenic and causes developmental defects such as axonal disorganization as well as skeletal abnormalities. Expression of PDIA3C57Y in the mouse hippocampus results in impaired synaptic plasticity and memory consolidation. Proteomic and functional analyses reveal that PDIA3C57Y expression leads to dysregulation of cell adhesion and actin cytoskeleton dynamics, associated with altered integrin biogenesis and reduced neuritogenesis. Biochemical studies show that PDIA3C57Y has decreased catalytic activity and forms disulfide-crosslinked aggregates that abnormally interact with chaperones in the endoplasmic reticulum. Thus, rare disease gene variant can provide insight into how perturbations of neuronal proteostasis can affect the function of the nervous system.
Subject(s)
Developmental Disabilities/genetics , Endoplasmic Reticulum/metabolism , Protein Disulfide-Isomerases/genetics , Proteostasis , Adolescent , Adult , Animals , Axons/metabolism , Axons/pathology , Cell Adhesion , Cells, Cultured , Child , Cytoskeleton/metabolism , Developmental Disabilities/metabolism , Developmental Disabilities/pathology , Female , Hippocampus/metabolism , Hippocampus/pathology , Humans , Integrins/metabolism , Male , Mice , Mice, Inbred C57BL , Mutation, Missense , Neuronal Outgrowth , Neuronal Plasticity , Pedigree , Protein Disulfide-Isomerases/metabolism , ZebrafishABSTRACT
Diet play an important role in the development of cancer. A lot of research has been done on the role of individual nutrients or phytochemicals and cancer risk. Both harmful and beneficial associations of this nutrient have been observed with cancer. However, there is an interaction of individual dietary constituents to influence disease risk. On the other hand, examining the diet as a whole as is done in dietary patterns research may produce more accurate estimates and data that can be more easily translated into dietary recommendations. Dietary patterns and cancer research are becoming increasingly common in the epidemiology literature, and novel dietary patterns are being generated at a rapid pace. However, major issues remain over whether one general "healthy" dietary pattern can be suggested for cancer prevention or whether several diets should be advocated for different forms of cancer protection. It is challenging to study typical human diet in animal model that is appropriate for cancer prevention. Some dietary patterns, such as the ketogenic diet or macronutrient composition alteration, have been investigated more extensively in animal models than in humans in terms of cancer prevention, and bigger human observational studies are now needed to advise dietary guidelines. The question of whether to adapt nutritional guidelines to population subgroups based on susceptibility factors (for example, family history, sex, age, other lifestyle factors or comorbidities, metabolomics signatures, or microbiota-based profiles) is still open and will be crucial in moving the field forward.
Subject(s)
Diet , Neoplasms , Humans , Neoplasms/prevention & control , Neoplasms/etiology , Diet/adverse effects , Animals , Dietary PatternsABSTRACT
Gut microbes are important and may play important role in spreading cancers specially the gastrointestinal malignancies preferably colorectal cancers. Gut microbes and diet can influence the tissues in gastrointestinal tract increasing the risk of cancer spread. Insufficient nutrient intake and imbalance diet can disturb the microbiome of gastrointestinal tract causing metabolism of xenobiotics which is beneficial as well as detrimental. Dietary imbalance may also weaken the immune system which is another reason for spreading and development of cancers. The triage of gut microbiome, host immune system, and dietary patterns may help the initiation of mechanism of carcinogenesis. In addition to its role in carcinogenesis and tumor development, there is still growing evidence as to how intestinal microflora influences the efficacy and toxicity of chemotherapy and immunotherapy by the gut microbiome. It can therefore be used as a biomarker to predict treatment response or poor response and can also be modified to improve cancer treatment.
Subject(s)
Diet , Gastrointestinal Microbiome , Neoplasms , Humans , Gastrointestinal Microbiome/physiology , Neoplasms/microbiology , AnimalsABSTRACT
Nodal regions, areas of intensive contact between Schwann cells and axons, may be exceptionally vulnerable to diabetes-induced changes because they are exposed to and impacted by the metabolic implications of diabetes. Insulin receptors, glucose transporters, Na+ and K+ channels, and mitochondria are abundant in nodes, all of which have been linked to the development and progression of Diabetic Peripheral Neuropathy (DPN) and Type 1 Diabetes Mellitus (T1DM)-associated cognitive impairment. Our study aimed to evaluate if the administration of Nigella sativa (NS) and Cassia angustifolia (CA) prevented diabetes-associated nervous system deficits in hyperglycemic mice. We developed T1DM mice through Streptozotocin (STZ) injections and validated the elevations in blood glucose levels. NS and CA were administered immediately upon the induction of diabetes. Behavioral analysis, histopathological evaluations, and assessment of molecular biomarkers (NR2A, MPZ, NfL) were performed to assess neuropathy and cognitive impairment. Improvements in memory, myelin loss, and the expression of synaptic proteins, even with the retention of hyperglycemia, were evident in the mice who were given a dose of herbal products upon the detection of hyperglycemia. NS was more beneficial in preventing memory impairments, demyelination, and synaptic dysfunction. The findings indicate that including these herbs in the diets of diabetic as well as pre-diabetic patients can reduce complications associated with T1DM, notably diabetic peripheral neuropathy and cognitive deficits associated with T1DM.
Subject(s)
Cognitive Dysfunction , Diabetic Neuropathies , Nigella sativa , Animals , Diabetic Neuropathies/drug therapy , Diabetic Neuropathies/prevention & control , Nigella sativa/chemistry , Mice , Cognitive Dysfunction/drug therapy , Cognitive Dysfunction/prevention & control , Cognitive Dysfunction/etiology , Male , Diabetes Mellitus, Experimental/complications , Diabetes Mellitus, Experimental/drug therapy , Plant Extracts/pharmacology , Plants, Medicinal/chemistry , Senna PlantABSTRACT
The blood-brain barrier (BBB) prevents the use of many drugs for the treatment of neurological disorders. Recently, nitrogen-doped carbon dots (NCDs) have emerged as promising nanocarriers to cross BBB. The primary focus of our study was to evaluate the effectiveness of NCDs for the symptomatic treatment of Alzheimer's disease (AD). In this study, we developed and characterized NCDs bound to rutin, a flavonoid with known benefits for AD. Despite its benefits, the transportation of rutin via NCDs for AD therapy has not been explored previously. We characterized the particles using FTIR and UV-visible spectroscopy followed by atomic force microscopy. Once the design was optimized and validated, we performed in vivo testing via a hemolytic assay to optimize the dosage. Preliminary in vitro testing was performed in AlCl3-induced rat models of AD whereby a single dose of 10 mg/kg NCDs-rutin was administered intraperitoneally. Interestingly, this single dose of 10 mg/kg NCDs-rutin produced the same behavioral effects as 50 mg/kg rutin administered intraperitoneally for 1 month. Similarly, histological and biomarker profiles (SOD2 and TLR4) also presented significant protective effects of NCDs-rutin against neuronal loss, inflammation, and oxidative stress. Hence, NCDs-rutin are a promising approach for the treatment of neurological diseases.
Subject(s)
Alzheimer Disease , Carbon , Glucose , Nitrogen , Rutin , Rutin/pharmacology , Rutin/chemistry , Animals , Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Carbon/chemistry , Carbon/pharmacology , Nitrogen/chemistry , Rats , Glucose/metabolism , Male , Quantum Dots/chemistry , Disease Models, Animal , Oxidative Stress/drug effects , HumansABSTRACT
Considerable advances in the field of cancer have been made; however, these have not been translated into similar clinical progress which results in the high prevalence and increased cancer-related mortality rate worldwide. Available treatments have several challenges such as off-target side effects, non-specific long-term potential biodisruption, drug resistance, and overall inadequate response rates and high probability of recurrence. The limitations associated with independent cancer diagnosis and therapy can be minimized by an emerging interdisciplinary research field of nanotheranostics which include successful integration of diagnosis and therapy on a single agent using nanoparticles. This may offer a powerful tool in developing innovative strategies to enable "personalized medicine" for diagnosis and treatment of cancer. Nanoparticles have been proven to be powerful imaging tools or potent agents for cancer diagnosis, treatment, and prevention. The nanotheranostic provides minimally invasive in vivo visualization of drug biodistribution and accumulation at the target site with real-time monitoring of therapeutic outcome. This chapter intends to cover several important aspects and the advances in the field of nanoparticles-mediated cancer therapeutics including nanocarrier development, drug/gene delivery, intrinsically active nanoparticles, tumor microenvironment, and nanotoxicity. The chapter represents an overview of challenges associated with cancer treatment, rational for nanotechnology in cancer therapeutics, novel concepts of multifunctional nanomaterials for cancer therapy along with their classification and their clinical prospective in different cancers. A special focus is on the nanotechnology: regulatory perspective for drug development in cancer therapeutics. Obstacles hindering further development of nanomaterials-mediated cancer therapy are also discussed. In general, the objective of this chapter is to improve our perceptive in the design and development of nanotechnology for cancer therapeutics.
Subject(s)
Drug-Related Side Effects and Adverse Reactions , Neoplasms , Humans , Prospective Studies , Tissue Distribution , Precision Medicine , Tumor MicroenvironmentABSTRACT
Targeted therapy and personalized medicine are novel emerging disciplines of cancer research intended for treatment and prevention. One of the most significant advancements in modern oncology is the shift from an organ-centric strategy to a personalized strategy guided by deep molecular analysis. This shift in view, which focuses on the tumour's precise molecular changes, has paved the way for individualized treatment. Researchers and clinicians are using targeted therapies to select the best treatment available based on the molecular characterization of malignant cancer. In the treatment of a cancer, personalized medicine entails the use of genetic, immunological, and proteomic profiling to provide therapeutic alternatives as well as prognostic information about cancer. In this book, targeted therapies and personalized medicine have been covered for specific malignancies, including latest FDA-approved targeted therapies and it also sheds light on effective anti-cancer regimens and drug resistance. This will help to enhance our ability to conduct individualized health planning, make early diagnoses, and choose optimal medications for each cancer patient with predictable side effects and outcomes in a quickly evolving era. Various applications and tools' capacity have been improved for early diagnosis of cancer and the growing number of clinical trials that choose specific molecular targets reflects this predicament. Nevertheless, there are several limitations that must need to be addressed. Hence, in this chapter, we will discuss recent advancements, challenges, and opportunities in personalized medicine for various cancers, with a specific emphasis on target therapies in diagnostics and therapeutics.
Subject(s)
Drug-Related Side Effects and Adverse Reactions , Precision Medicine , United States , Humans , Proteomics , Health Planning , Medical OncologyABSTRACT
We present a Pakistani kinship afflicted with a syndrome with features including short stature, reduced sitting height, orofacial symptoms including prominent forehead and thick eyebrows, short and broad thorax, and variable features such as long philtrum, short broad neck, barrel chest, thoracic kyphoscoliosis, hypogonadism, and hypospadias. Phenotypic variation even within different sibships was considerable. The unique combination of the phenotypic characteristics prompted us to determine the shared homozygosity regions in patient genomes and the pathogenic variants by next generation technologies like single nucleotide polymorphism (SNP) genotyping and whole exome sequencing (WES). Through these analyses, we detected homozygous OBSL1 c.848delG (p.Gly283AlafsTer54) as the causal variant. Biallelic variants in OBSL1 are known to cause Three M Syndrome 2 (3M2), a rare disorder of growth retardation with characteristic facial dysmorphism and musculoskeletal abnormalities. Affected members of the family do not have the 3M2 hallmark features of dolichocephaly, hypoplastic midface, anteverted nares, low nasal bridge, pectus excavatum, sacral hyperlordosis, spina bifida occulta, anterior wedging of thoracic vertebrae, prominent heels, and prominent talus. Moreover, they have some variable features not typical for the syndrome such as round face, disproportionate short stature, barrel chest, thoracic kyphoscoliosis, hypogonadism, and hypospadias. Our study facilitated genetic diagnosis in the family, expanded the clinical phenotype for 3M2, and unraveled the considerable clinical variation within the same kinship. We conclude that unbiased molecular analyses such as WES should be more integrated into healthcare, particularly in populations with high parental consanguinity, given the potential of such analyses to facilitate diagnosis.
Subject(s)
Hypogonadism , Hypospadias , Male , Humans , Mutation/genetics , Phenotype , Hypogonadism/genetics , Cytoskeletal Proteins/geneticsABSTRACT
Laron syndrome (LS) is a rare autosomal recessively segregating disorder of severe short stature. The condition is characterized by short limbs, delayed puberty, hypoglycemia in infancy, and obesity. Mutations in growth hormone receptor (GHR) have been implicated in LS; hence, it is also known as growth hormone insensitivity syndrome (MIM-262500). Here we represent a consanguineous Pakistani family in which three siblings were afflicted with LS. Patients had rather similar phenotypic presentations marked with short stature, delayed bone age, limited extension of elbows, truncal obesity, delayed puberty, childish appearance, and frontal bossing. They also had additional features such as hypo-muscularity, early fatigue, large ears, widely-spaced breasts, and attention deficit behavior, which are rarely reported in LS. The unusual combination of the features hindered a straightforward diagnosis and prompted us to first detect the regions of shared homozygosity and subsequently the disease-causing variant by next generation technologies, like SNP genotyping and exome sequencing. A homozygous pathogenic variant c.508G>C (p.(Asp170His)) in GHR was detected. The variant is known to be implicated in LS, supporting the molecular diagnosis of LS. Also, we present detailed clinical, hematological, and hormonal profiling of the siblings.
Subject(s)
Laron Syndrome , Puberty, Delayed , Humans , Laron Syndrome/genetics , Laron Syndrome/diagnosis , Mutation/genetics , Obesity , Pakistan , Receptors, Somatotropin/geneticsABSTRACT
Intellectual disability (ID) involves compromised intellectual, learning and cognitive skills, and behavioral capabilities with reduced psychomotor skills. One of the preventable causes of ID is congenital hypothyroidism (CH), which may be due to biallelic mutations in thyroid peroxidase (TPO). In low- and middle-income countries with no newborn screening programs, CH poses a great risk of ID and long-term morbidity. We report two large Pakistani families with a total of 16 patients afflicted with CH. Detailed clinical and behavioral assessments, SNP-based homozygosity mapping, linkage analysis, and exome sequencing were performed. Initially, affected individuals were referred as suffering ID (in 11 of 16 patients) and developmental delay (in 14). Secondary/associated features were verbal apraxia (in 13), goiter (in 12), short stature (in 11), limb hypotonia (in 14), no pubertal onset (five of 10 of age ≥14 years), high myopia (in eight), muscle cramps (in six), and in some, variable microcephaly and enuresis/encopresis, fits, chronic fatigue, and other behavioral symptoms, which are not characteristics of CH. Molecular genetic analyses led to the discovery of homozygous variants in TPO: novel missense variant c.719A>G (p.Asp240Gly) in family 1 and rare c.2315A>G (p.Tyr772Cys) in family 2. In low-resource countries where neonatal screening programs do not include a CH test, the burden of neurodevelopmental disorders is likely to be increased due to untreated CH. Secondly, in the background of the high prevalence of recessive disorders due to high parental consanguinity, the severe manifestation of TPO-deficiency mimics a wide range of neurological and other presentations posing a diagnostic dilemma.
Subject(s)
Congenital Hypothyroidism , Intellectual Disability , Adolescent , Child , Humans , Congenital Hypothyroidism/complications , Congenital Hypothyroidism/diagnosis , Congenital Hypothyroidism/genetics , Developmental Disabilities/diagnosis , Developmental Disabilities/genetics , Hearing , Intellectual Disability/diagnosis , Intellectual Disability/genetics , Iodide Peroxidase/genetics , Mutation/geneticsABSTRACT
Spondylocarpotarsal synostosis (SCT) syndrome is a very rare and severe form of skeletal dysplasia. The hallmark features of SCT are disproportionate short stature, scoliosis, fusion of carpal and tarsal bones, and clubfoot. Other common manifestations are cleft palate, conductive and sensorineural hearing loss, joint stiffness, and dental enamel hypoplasia. Homozygous variants in FLNB are known to cause SCT. This study was aimed to investigate the phenotypic and genetic basis of unique presentation of SCT syndrome segregating in a consanguineous Pakistani family. Three of the four affected siblings evaluated had severe short stature, short trunk, short neck, kyphoscoliosis, pectus carinatum, and winged scapula. The subjects had difficulty in walking and gait problems and complained of knee pain and backache. Roentgenographic examination of the eldest patient revealed gross anomalies in the axial skeleton including thoracolumbar and cervical fusion of ribs, severe kyphoscoliosis, thoracic and lumbar lordosis, coxa valga, fusion of certain carpals and tarsals, and clinodactyly. The patients had normal faces and lacked other typical features of SCT like cleft palate, conductive and sensorineural hearing loss, joint stiffness, and dental enamel hypoplasia. Whole exome sequencing (WES) of two affected siblings led to the discovery of a rare stop-gain variant c.220C>T (p.(Gln74*)) in exon 1 of the FLNB gene. The variant was homozygous and segregated with the malformation in this family. This study reports extensive phenotypic variability in SCT and expands the mutation spectrum of FLNB.
Subject(s)
Cleft Palate , Dental Enamel Hypoplasia , Scoliosis , Animals , Humans , Scoliosis/diagnostic imaging , Scoliosis/genetics , Consanguinity , Phenotype , Filamins/geneticsABSTRACT
Objective: Congenital anomalies (CA) or birth defects cause substantial healthcare burden in developing countries. There are few studies from Pakistan on the prevalence-pattern of CA. The purpose of this study was to determine the prevalence-pattern and genetic attributes of CA at a tertiary care facility in Rawalpindi, Pakistan. Methods: In a cross-sectional study design, patients with CA were ascertained from Pediatric and Neonatal Section of Holy Family Hospital, Rawalpindi from March-2022 to June-2022. International Classification of Diseases (ICD-10) and Online Mendelian Inheritance in Man (OMIM) databases were utilized for uniformity in classification. The pattern of CA as well as familial/sporadic nature, syndromic/isolated presentations, and prenatal consanguinity were estimated. Descriptive summaries were generated. Results: A total of 517 independent cases with certain types of CA were recruited. There were eight major and 70 minor categories. Among the major categories, neurological disorders (39.1%) were predominating followed by neuromuscular disorders (21.1%), limb defects (13.5%), musculoskeletal defects (7.4%), blood disorders (4.3%), orofacial defects (3.9%), metabolic disorders (3.7%), and Others (7.1%). The sporadic cases were in majority (72.5%) compared to familial cases (27.5%). Further, 63% patients had syndromic presentations and there were 37% cases with isolated appearances. A total of 70% cases had parental consanguinity. Conclusion: The majority of anomalies were of preventable nature and certain healthcare measures including antinatal care and counseling can be adopted to minimize their burden. Additionally, there is an urgent need to raise awareness of the negative consequences of consanguineous marriages, which constitute a significant risk factor in cases with inherited CA.
ABSTRACT
BACKGROUND: Bardet-Biedl syndrome (BBS) is a ciliopathy with extensive phenotypic variability and genetic heterogeneity. We aimed to discover the gene mutated in a consanguineous kindred with multiple cases of a BBS phenotype. METHODS: SNP genotype data were used for linkage analysis and exome sequencing to identify mutations. Modelling and in silico analysis were performed to predict mutation severity. RESULTS: Patients had postaxial polydactyly plus variable other clinical features including rod-cone dystrophy, obesity, intellectual disability, renal malformation, developmental delay, dental anomalies, speech disorder and enlarged fatty liver. The 4.57 Mb disease locus harboured homozygous, truncating CEP19 c.194_195insA (p.Tyr65*) mutation. We also found glioma-associated oncogene homolog 1(GLI1) c.820G>C (p.Gly274Arg) in the homozygous state in most patients. In silico modelling strongly suggests that it is damaging. Also, different combinations of four possible modifier alleles in BBS-related genes were detected. Two are known modifier alleles for BBS, splicing variant CCDC28B c.330C>T and missense MKKS/BBS6 p.Ile339Val, and the others are C8ORF37/BBS21 p.Ala178Val and TMEM67/BBS14 modifier p.Asp799Asp. Some patients carry all those five known/possible modifier alleles. Such variants are highly significantly more abundant in our patients than in a control group. CONCLUSION: CEP19 encodes a centrosomal and ciliary protein, as all BBS genes do. Another truncating mutation p.Arg82* has been reported as responsible for morbid obesity in a family; however, in the family we present, not all homozygotes are obese, although some are severely obese. The variant in GLI1, encoding a transcription factor that localises to the primary cilium and nucleus and is a mediator of the sonic hedgehog pathway, possibly exacerbates disease severity when in the homozygous state.
Subject(s)
Bardet-Biedl Syndrome/genetics , Cell Cycle Proteins/genetics , Fingers/abnormalities , Obesity, Morbid/genetics , Polydactyly/genetics , Toes/abnormalities , Zinc Finger Protein GLI1/genetics , Adolescent , Adult , Bardet-Biedl Syndrome/complications , Bardet-Biedl Syndrome/pathology , Female , Fingers/pathology , Genetic Linkage , Homozygote , Humans , Male , Middle Aged , Mutation , Obesity, Morbid/pathology , Polydactyly/complications , Polydactyly/pathology , Polymorphism, Single Nucleotide/genetics , Toes/pathology , Exome Sequencing/methods , Young AdultABSTRACT
Mesoaxial synostotic syndactyly, Malik-Percin type (MSSD) (syndactyly type IX) is a rare autosomal-recessive nonsyndromic digit anomaly with only two affected families reported so far. We previously showed that the trait is genetically distinct from other syndactyly types, and through autozygosity mapping we had identified a locus on chromosome 17p13.3 for this unique limb malformation. Here, we extend the number of independent pedigrees from various geographic regions segregating MSSD to a total of six. We demonstrate that three neighboring missense mutations affecting the highly conserved DNA-binding region of the basic helix-loop-helix A9 transcription factor (BHLHA9) are associated with this phenotype. Recombinant BHLHA9 generated by transient gene expression is shown to be located in the cytoplasm and the cell nucleus. Transcription factors 3, 4, and 12, members of the E protein (class I) family of helix-loop-helix transcription factors, are highlighted in yeast two-hybrid analysis as potential dimerization partners for BHLHA9. In the presence of BHLHA9, the potential of these three proteins to activate expression of an E-box-regulated target gene is reduced considerably. BHLHA9 harboring one of the three substitutions detected in MSSD-affected individuals eliminates entirely the transcription activation by these class I bHLH proteins. We conclude that by dimerizing with other bHLH protein monomers, BHLHA9 could fine tune the expression of regulatory factors governing determination of central limb mesenchyme cells, a function made impossible by altering critical amino acids in the DNA binding domain. These findings identify BHLHA9 as an essential player in the regulatory network governing limb morphogenesis in humans.
Subject(s)
Basic Helix-Loop-Helix Transcription Factors/genetics , Fingers/abnormalities , Mutation, Missense , Syndactyly/genetics , Toes/abnormalities , Amino Acid Sequence , Binding Sites , DNA Mutational Analysis , Dimerization , Female , Genes, Reporter , Genotype , Haplotypes , Humans , Italy , Male , Middle Aged , Pakistan , Pedigree , Phenotype , Protein Binding , Protein Structure, Tertiary , Sequence Alignment , Turkey , Young AdultABSTRACT
We report on nine members of a consanguineous Pakistani family with primary presentation of intellectual disability, developmental delay, limb and gait ataxia, behavioral and speech problems, and tremor. By linkage mapping and exome sequencing we identified novel homozygous splicing variant c.6375-1G>C in SPTBN2. To date, only two other SPTBN2 mutations with recessive pattern of inheritance causing SCAR14 (spinocerebellar ataxia, autosomal recessive 14) that manifest with developmental ataxia and cognitive impairment, or cerebellar ataxia, mental retardation, and pyramidal signs have been reported. The mutation we identified is predicted to lead to the deletion of just the pleckstrin homology domain; thus, the earlier onset and more progressive nature of the disease in the presented family, as compared to earlier reports, were unexpected. No other mutation that could possibly explain the features that were unusual for SCAR14-arched palate, limb hypotonia, climacophobia, and behavioral problems-was identified. The disease was more severe in males than females. Our findings expand the recessive SPTBN2 mutation phenotype. We also review SPTBN2 mutation phenotypes. The gene encodes beta-III spectrin, which forms tetramers with alpha-II spectrin. The manifestations of this third recessive mutation suggest that for recessive mutations either no mutant protein is synthesized because the transcript is subject to nonsense-mediated decay or the mutant protein does not bind membrane proteins and, thus, does not exert a negative effect in heterozygotes, whereas the dominant mutations causing SCA5 form defective tetramers that compete with the native tetramers in binding membrane proteins, but are unable to anchor them.
Subject(s)
Developmental Disabilities/genetics , Spectrin/genetics , Spinocerebellar Ataxias/genetics , Tremor/genetics , Adolescent , Adult , Child , Child, Preschool , Developmental Disabilities/physiopathology , Female , Homozygote , Humans , Language Development Disorders/genetics , Language Development Disorders/physiopathology , Magnetic Resonance Imaging , Male , Phenotype , Problem Behavior , Sequence Deletion , Spinocerebellar Ataxias/diagnostic imaging , Spinocerebellar Ataxias/physiopathology , Tremor/physiopathology , Young AdultABSTRACT
Primary microcephaly is clinically variable and genetically heterogeneous. Four phenotypically distinct types of autosomal recessive microcephaly syndromes are due to different RBBP8 mutations. We report on a consanguineous Pakistani family with homozygous RBBP8 mutation c.1808_1809delTA (p.Ile603Lysfs*7) manifesting microcephaly and a distinct combination of skeletal, limb and ectodermal defects, mild intellectual disability, minor facial anomalies, anonychia, disproportionate short stature and brachydactyly, and additionally talipes in one patient.
Subject(s)
Brachydactyly/genetics , Carrier Proteins/genetics , Dwarfism/genetics , Intellectual Disability/genetics , Microcephaly/genetics , Mutation/genetics , Nuclear Proteins/genetics , Adolescent , Adult , Brachydactyly/pathology , Consanguinity , Dwarfism/pathology , Endodeoxyribonucleases , Female , Homozygote , Humans , Intellectual Disability/pathology , Male , Microcephaly/pathology , Pedigree , Phenotype , Prognosis , Syndrome , Young AdultABSTRACT
Grebe syndrome (OMIM-200700) is a very rare type of acromesomelic dysplasia with autosomal recessive inheritance. We studied a Pakistani family with two affected individuals having typical features of Grebe chondrodysplasia. Patients were observed with short and deformed limbs having a proximo-distal gradient of severity. Hind-limbs were more severely affected than fore-limbs. Digits on autopods were very short and nonfunctional. Index subject also had nearsightedness. However, symptoms in the craniofacial and axial skeleton were minimal. Genetic analysis revealed four base pair insertion mutation (c.1114insGAGT) in gene coding cartilage-derived morphogenetic protein-1 (CDMP1). This mutation was predicted to cause premature stop codon. The clinical presentation in this study broadens the range of phenotypes associated with CDMP1 mutation in Pakistani population.
ABSTRACT
Congenital hypoplasia of thumb is rare malformation which is less likely to appear as an isolated entity. Four independent subjects exhibiting various grades of underdeveloped first digital ray were recruited. The affected autopods had narrow palms, medial or valgus inclinations of index fingers and thenar weakness, while the postaxial digits were least affected. According to the classification of hypoplastic thumb by Blauth and Schneider-Sickert (1981), the phenotypes were concordant with types 3 and 4. In one of the subjects there was contralateral preaxial polydactyly. All cases were sporadic and nonsyndromic and parental consanguinity was witnessed in two individuals. Recurrent appearance of similar phenotypes may suggest genetic etiologies which should be elucidated with the help of high-throughput genetic methods.
ABSTRACT
Meningomyelocele is one of the most severe forms of neural tube defects (NTDs) and the most frequent structural birth defect of the central nervous system. We assembled the Spina Bifida Sequencing Consortium to identify causes. Exome and genome sequencing of 715 parent-offspring trios identified six patients with chromosomal 22q11.2 deletions, suggesting a 23-fold increased risk compared with the general population. Furthermore, analysis of a separate 22q11.2 deletion cohort suggested a 12- to 15-fold increased NTD risk of meningomyelocele. The loss of Crkl, one of several neural tube-expressed genes within the minimal deletion interval, was sufficient to replicate NTDs in mice, where both penetrance and expressivity were exacerbated by maternal folate deficiency. Thus, the common 22q11.2 deletion confers substantial meningomyelocele risk, which is partially alleviated by folate supplementation.
Subject(s)
Chromosome Deletion , Chromosomes, Human, Pair 22 , Meningomyelocele , Animals , Female , Humans , Male , Mice , Chromosomes, Human, Pair 22/genetics , DiGeorge Syndrome/genetics , Exome Sequencing , Folic Acid/administration & dosage , Folic Acid Deficiency/complications , Folic Acid Deficiency/genetics , Meningomyelocele/epidemiology , Meningomyelocele/genetics , Penetrance , Spinal Dysraphism/genetics , Risk , Adaptor Proteins, Signal Transducing/geneticsABSTRACT
With the onset of coronavirus disease in December 2019, the normal routine and lifestyle of the humans has adversely affected all over the world. This change in lifestyle not only increased the level of stress and anxiety, but also badly modified the eating habits during the lockdown period. This increased the rate of binge eating disorder in people who were already immune-compromised. This rapid communication aims to develop awareness among people to stay calm during this pandemic and eat healthy.