RESEARCH

From Molecular Genetics to Translational Therapeutics

Genetics of inherited disorders

Genetics and Functional Studies of Autosomal Recessive Neurological Disorders

Neurological conditions account for over 6% of the global disease burden. There are more than 600 neurological disorders, and cognitive dysfunction, also referred to as intellectual disability (ID), occupies a prominent position in this list. Cognitive dysfunction arises from the failure of neuronal cells to organize into a complex network and remodel this network in response to learning and experience. It is manifested by deficits in adaptive behaviors in everyday social and practical skills. Due to its high prevalence, and the lifetime cost of care per individual in the range of $1-2 million in the United States (CDC), it presents a significant health burden.

An emerging understanding of ID posits a seed genetic cause that escalates across the scales and networks of the nervous system into a systems-level perturbation of information processing in multiple brain areas, leading to pathologies of cognition. Etiopathogenesis can be found in one protein often implicated in various cellular processes and developmental stages. During the interdependent processes of brain circuit development, these perturbations cause cascades of dysfunction that ripple across the molecular and cellular scales and scales of neuronal connectivity, from synaptic nanostructure to transmission to mesoscale neuroanatomical connectivity. Monogenic ID, therefore, presents a rare opportunity to appreciate the tiers of causality in diseases of cognition and those of neurotypical brain development when investigated across scales and developmental time.

Dr. Saima Riazuddin and her collaborators, including Drs. Thomas Blanpied and Alex Poulopoulos at UMB have team synergy to investigate ID from its genetic to its circuit miswiring etiologies by interrogating distinct cell types (cellular scale), the composition and distribution of molecular complexes (nanoscale), and the connectivity networks they develop across the brain (mesoscale), investigated in variety systems and developmental times. We use this integrated approach as a proof-of-principal pipeline for the investigation of nervous system diseases stemming from monogenic causes that lead to complex cognitive impairment.

Animal models

Deciphering the Molecular Mechanisms of the Inner ear and Middle ear Development and Function

Role of CIB Proteins in the Inner Ear Structure and Function

Hearing loss (HL) is an etiologically diverse condition that can occur at any age and severity level, affecting 1 in 500 infants and more than 360 million people globally. In numerous ethnicities, Dr. Ahmed and his team have previously identified pathogenic variants in the CIB2 gene encoding Calcium and Integrin-Binding protein 2 (CIB2) as the etiology of HL. In collaboration with Dr. Gregory Frolenkov at the University of Kentucky, his team discovered that CIB2 is expressed in the mouse hair cell stereocilia and binds to the TMC1 and TMC2 components of the hair cell mechanoelectrical transduction (MET) complex and that deafness causing CIB2 mutations disrupt these interactions and concluded that CIB2 is essential for the MET function. His team has generated two mouse models carrying the human deafness-related Cib2 variants (Cib2^F91S and Cib2^R186W knock-ins) and characterized them together with a mouse line lacking CIB2 (Cib2^ko). Both Cib2^F91S and Cib2ko mouse strains are deaf and lack typical MET responses in the auditory hair cells despite the existence of tip links that are ordinarily responsible for gating the MET channels. In contrast, the p.R186W mutation does not disrupt the interaction between CIB2 and TMC1/2 and MET currents in mutant mice are diminished but still detectable. It is particularly intriguing that CIB2’s participation in the MET machinery may be responsible for at least some of the several well-known effects of Ca²⁺ on hair cell MET function. Currently, his team, in collaboration with Dr. Frolenkov, is investigating the precise function of CIB2 in MET. Their working hypothesis is that CIB2 is a calcium-dependent element that regulates the sensitivity of the MET channels and force transmission to these channels in the mammalian auditory hair cells.

Their findings further determined that CIB2 deficiency causes an overgrowth of transducing shorter-row stereocilia in the hair bundle without altering the non-transducing tallest-row stereocilia. This observation cannot be explained solely by the loss of MET since blockage of the MET channels causes an opposite effect, the retraction of transducing stereocilia. Hence, CIB2 must have some role in stereocilia growth, unrelated to MET. Currently, they are investigating the involvement of CIB2 in the molecular networks implicated in the development and patterning of auditory stereocilia bundles. Besides CIB2, Dr. Ahmed’s team is also investigating the role of CIB3 in the auditory and vestibular hair cells.