A5032485991- Hearing, Cochlea, Tinnitus, Genetics
- Genomics and Rare Diseases
- Vestibular and auditory disorders
- Ear Surgery and Otitis Media
- Connexins and lens biology
- Ion Channels and Receptors
- Hearing Loss and Rehabilitation
- Cell Adhesion Molecules Research
- Cellular transport and secretion
- melanin and skin pigmentation
- Plant Molecular Biology Research
- Plant Virus Research Studies
- Barrier Structure and Function Studies
- Biochemical Analysis and Sensing Techniques
- Cancer Genomics and Diagnostics
- Genetics and Neurodevelopmental Disorders
- Congenital heart defects research
- RNA regulation and disease
- Genomic variations and chromosomal abnormalities
- Nicotinic Acetylcholine Receptors Study
- Landslides and related hazards
- Epigenetics and DNA Methylation
- Fibromyalgia and Chronic Fatigue Syndrome Research
- Glycogen Storage Diseases and Myoclonus
- Human Health and Disease
National Institute on Deafness and Other Communication Disorders
2020-2024
National Institutes of Health
2020-2024
PerkinElmer (United States)
2023
Laboratory of Molecular Genetics
2021
Combined Military Hospital
2021
National University of Medical Sciences
2021
Cyber Defense Agency (United States)
2019
University of Maryland, Baltimore
2015-2018
University of Azad Jammu and Kashmir
2018
COMSATS University Islamabad
2014
The two compositionally distinct extracellular cochlear fluids, endolymph and perilymph, are separated by tight junctions that outline the scala media reticular lamina. Mutations in TRIC (also known as MARVELD2), which encodes a tricellular junction protein tricellulin, lead to nonsyndromic hearing loss (DFNB49). We generated knockin mouse carries mutation orthologous coding linked DFNB49 humans. Tricellulin was absent from inner ear epithelia of mutant animals, developed rapidly progressing...
Autosomal recessive nonsyndromic hearing loss is a genetically heterogeneous disorder. Here, we report severe-to-profound sensorineural locus, DFNB100 on chromosome 5q13.2-q23.2. Exome enrichment followed by massive parallel sequencing revealed c.2510G>A transition variant in PPIP5K2 that segregated with DFNB100-associated two large apparently unrelated Pakistani families. PPIP5Ks enzymes interconvert 5-IP7 and IP8, key members of the inositol pyrophosphate (PP-IP) cell-signaling family....
A modifier variant can abrogate the risk of a monogenic disorder. DFNM1 is locus on chromosome 1 encoding dominant suppressor human DFNB26 recessive, profound deafness. Here, we report that associated with substitution (p.Gly116Glu) in pleckstrin homology domain GRB2-associated binding protein (GAB1), an essential scaffold MET proto-oncogene, receptor tyrosine kinase/HGF (MET/HGF) pathway. (p.Arg544Gln) METTL13, predicted methyltransferase, GAB1-associated In zebrafish, METTL13 mRNA...
Abstract Usher syndrome has been historically categorized into one of three classical types based on the patient phenotype. However, vestibular phenotype does not infallibly predict which genes are mutated. Conversely, genotype is sufficient to reliably function. Here we present a characterization 90 patients with clinical presentation (59 females), aged 10.9 75.5 years, genetic variants in eight syndromic and expand description atypical syndrome. We identified unexpected horizontal...
Although the clinical utility of genome sequencing for critically ill children is well recognized, its proactive pediatric screening not explored.To evaluate molecular findings from ostensibly healthy with compared a gene panel medically actionable conditions.This case series study was conducted among consecutive, apparently undergoing genetic disorders by (n = 562) or an exome-based 268 genes 606) March 1, 2018, through July 31, 2022.Genetic pediatric-onset using genes.Molecular indicative...
Hereditary deafness and retinal dystrophy are each genetically heterogenous clinically variable. Three small unrelated families segregating the combination of were studied by exome sequencing (ES). The proband Family 1 was found to be compound heterozygous for NM_004525.3: LRP2: c.5005A > G, p.(Asn1669Asp) c.149C p.(Thr50Ser). In 2, two sisters LRP2 variants, p.(Tyr3933Cys) an experimentally confirmed c.7715 + 3A T consensus splice-altering variant. 3, is a donor splice site variant...
MAP3K1 is a serine/threonine kinase that activated by diverse set of stimuli and exerts its effect through various downstream affecter molecules, including JNK, ERK1/2 p38. In humans, mutant alleles are associated with 46, XY sex reversal. Until recently, the only phenotype observed in Map3k1tm1Yxia mice was open eyelids at birth. Here, we report homozygous have early-onset profound hearing loss accompanied progressive degeneration cochlear outer hair cells. mouse inner ear, has punctate...
Abstract Although variant alleles of hundreds genes are associated with sensorineural deafness in children, the and involved remain largely unknown Sub-Saharan regions Africa. We ascertained 56 small families mainly Yoruba ethno-lingual ancestry or near Ibadan, Nigeria, that had at least one individual nonsyndromic, severe-to-profound, prelingual-onset, bilateral hearing loss not attributed to nongenetic factors. performed a combination exome Sanger sequencing analyses evaluate both nuclear...
Hearing depends on intricate morphologies and mechanical properties of diverse inner ear cell types. The individual contributions various types into the organ Corti mechanisms their integration are yet largely unknown. Using sub-100-nm spatial resolution atomic force microscopy (AFM), we mapped Young’s modulus (stiffness) apical surface different cells freshly dissected P5–P6 cochlear epithelium from wild-type mice lacking either Trio F-actin binding protein (TRIOBP) isoforms 4 5 or isoform...
Hereditary deafness is clinically and genetically heterogeneous. We investigated segregating as a recessive trait in two families. Audiological examinations revealed an asymmetric mild to profound hearing loss with childhood or adolescent onset. Exome sequencing of probands identified homozygous c.475G>A;p.(Glu159Lys) variant CLDN9 (NM_020982.4) one family c.370_372dupATC;p.(Ile124dup) affected individual second family. Claudin 9 (CLDN9) integral membrane protein constituent epithelial...
Melanocortin 1 receptor (MC1R), a Gs protein-coupled of the melanocyte's plasma membrane, is major determinant skin pigmentation and phototype. Upon activation by α-melanocyte stimulating hormone, MC1R triggers cAMP cascade to stimulate eumelanogenesis. We used whole-exome sequencing identify causative alleles in Pakistani families with hair hypopigmentation. Six mutations segregated phenotype seven families, including p.Val174del in-frame deletion p.Tyr298* nonsense mutation, that were...
Early diagnosis of a genetic disease is critical to maximize clinical outcomes and reduce healthcare costs. Genome sequencing (GS) has shown great promise in rapidly providing for critically ill newborns moved into the spotlight national international initiatives that explore feasibility utility GS newborn screening (GS NBS). Higher diagnostic NBS compared limited number disease/gene screens may not necessarily translate higher utility.
Fabry disease (FD) is an X-linked progressive multisystemic lysosomal caused by pathogenic variants in the GLA gene encoding alpha-galactosidase A, which affects both males and heterozygous females. In US, FD was not recommended for Recommended Uniform Screening Panel (RUSP) due to concerns of variable clinical presentation, possible late onset, risk serious symptoms discernible newborns. Nevertheless, newborn screening (NBS) has now been implemented several states around world.
Deafness in vertebrates is associated with variants of hundreds genes. Yet, many mutant genes causing rare forms deafness remain to be discovered. A consanguineous Pakistani family segregating nonsyndromic two sibships were studied using microarrays and exome sequencing. 1.2 Mb locus (DFNB128) on chromosome 5q11.2 encompassing six was identified. In one the this family, a novel homozygous recessive variant NM_005921.2:c.4460G>A p.(Arg1487His) kinase domain
Mutations of human TBC1D24 are associated with deafness, epilepsy, or DOORS syndrome (deafness, onychodystrophy, osteodystrophy, cognitive disability, and seizures). The causal relationships between variants the different clinical phenotypes not understood. Our hypothesis is that phenotypic heterogeneity missense mutations results, in part, from perturbed binding protein partners. To discover novel partners TBC1D24, we conducted yeast two-hybrid (Y2H) screen using mouse full-length as bait....