Schimmenti, Lisa A.

Mitogen-Activated Protein 3 Kinase 7 (MAP3K7, MIM 602614) encodes the ubiquitously expressed transforming growth factor β (TGF-β)–activated kinase 1 (TAK1), which plays a crucial role in many cellular processes. Variants in the MAP3K7 gene have been linked to 2 distinct disorders: frontometaphyseal dysplasia type 2 (FMD2, MIM #617137) and cardiospondylocarpofacial syndrome (CSCF, MIM #157800). The fact that different variants can induce 2 distinct phenotypes suggests a phenotype/genotype correlation, but no side-by-side comparison has been done thus far to confirm this. Here we significantly expand the cohort and the description of clinical phenotypes for individuals with CSCF and FMD2 who carry variants in MAP3K7. We show that in contrast to FMD2-causing variants, CSCF-causing variants in MAP3K7 have a loss-of-function effect. Additionally, patients with pathogenic variants in MAP3K7 are at risk for cardiac disease, have symptoms associated with connective tissue disease and we show overlap in clinical phenotypes of CSCF with Noonan syndrome. Together, we provide evidence for a molecular fingerprint of FMD2- versus CSCF-causing MAP3K7 variants and conclude that variants in MAP3K7 should be considered in the differential diagnosis of patients with syndromic congenital cardiac defects and/or cardiomyopathy, syndromic connective tissue disorders and in the differential diagnosis of Noonan syndrome.

AbstractAn infant was referred for evaluation of congenital glaucoma and corneal clouding. In addition, he had a pelvic kidney, hypotonia, patent ductus arteriosus, abnormal pinnae, and developmental delay. Exome sequencing identified a previously unpublished de novo single nucleotide insertion in PBX1 c.400dupG (NM_002585.3), predicted to cause a frameshift resulting in a truncated protein with loss of function (p.Ala134Glyfs*65). Identification of this loss of function variant supports the diagnosis of congenital anomalies of the kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay (CAKUTHED). Here, we propose glaucoma as an extra‐renal manifestation associated with PBX1‐related disease due to the relationship of PBX1 with MEIS1, MEIS2, and FOXC1 transcription factors associated with eye development.

Two out of every thousand newborns are born deaf or hard of hearing. Sixty percent of hearing loss has an identifiable genetic cause. One of the most common forms of genetic hearing loss is Pendred syndrome. Disease causing genetic alterations or pathogenic variants in SLC26A4 are associated with Pendred Syndrome, a disorder characterized by bilateral sensorineural hearing loss and occasionally thyroid goiter. Patients with SLC26A4 pathogenic variants have an enlarged vestibular aqueduct, a malformation of the temporal bone. Pendrin, the protein product of SLC26A4 , is a solute carrier. Pendrin is expressed in the inner ear, thyroid, and kidney. In the inner ear, pendrin modulates the transport of bicarbonate and chloride, allowing bicarbonate to leave the supporting cells of the inner ear and chloride to enter. This helps maintain a relatively neutral pH environment in the inner ear. It is not known how the abnormal SLC26A4 protein products modulate hearing loss and contribute to temporal bone abnormalities. The goal of this study was to model SLC26A4 associated genetic hearing loss in zebrafish and elucidate a mechanism responsible for hearing loss in patients with pathogenic variants in SLC26A4 . To model the human condition, slc26a4 mutations in zebrafish were generated via transcription activator like effector nucleases (TALENs) at the site of the the most common SLC26A4 pathogenic variants. We obtained a 23bp deletion mutation in exon 10 of slc26a4 . We hypothesized that fish with biallelic slc26a4 mutations would closely recapitulate the human phenotype and have significant hearing loss and structural ear malformations. To test for deafness in zebrafish, we developed a hearing assessment which exposes larval or adult fish to specific sound stimuli while recording startle responses. To quantitatively study the slc26a4 mutant ear phenotype, we took measurements of the posterior and anterior otolith area and the ear area using bright field microscopy. Results indicate that homozygous embryos tested at 5 days post fertilization, the day of hearing onset in zebrafish, have hearing that was not different that wildype, however adult fish with two copies of mutated slc26a4 have frequency specific reduced responses at 400 Hz, 80db. These results indicate that slc26a4 mutants have progressive frequency specific hearing loss. Bright field imaging and measurement analysis showed that slc26a4 mutant larvae have significantly smaller standardized posterior otolith areas, anterior otolith areas, and ear areas on average compared to wildtype at 5dpf. This closely matches the human phenotype, as humans with SLC26A4 pathogenic variants may have progressive hearing loss and temporal bone abnormalities. Support or Funding Information Mayo Center for Individualized Medicine Mayo Clinic Department of Otorhinolaryngology NIH 5R25GM075148‐11 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

ABSTRACT The mariner (myo7aa−/−) mutant is a zebrafish model for Usher syndrome type 1 (USH1). To further characterize hair cell synaptic elements in myo7aa−/− mutants, we focused on the ribbon synapse and evaluated ultrastructure, number and distribution of immunolabeled ribbons, and postsynaptic densities. By transmission electron microscopy, we determined that myo7aa−/− zebrafish have fewer glutamatergic vesicles tethered to ribbon synapses, yet maintain a comparable ribbon area. In myo7aa−/− hair cells, immunolocalization of Ctbp2 showed fewer ribbon-containing cells in total and an altered distribution of Ctbp2 puncta compared to wild-type hair cells. myo7aa−/− mutants have fewer postsynaptic densities – as assessed by MAGUK immunolabeling – compared to wild-type zebrafish. We quantified the circular swimming behavior of myo7aa−/− mutant fish and measured a greater turning angle (absolute smooth orientation). It has previously been shown that L-type voltage-gated calcium channels are necessary for ribbon localization and occurrence of postsynaptic density; thus, we hypothesized and observed that L-type voltage-gated calcium channel agonists change behavioral and synaptic phenotypes in myo7aa−/− mutants in a drug-specific manner. Our results indicate that treatment with L-type voltage-gated calcium channel agonists alter hair cell synaptic elements and improve behavioral phenotypes of myo7aa−/− mutants. Our data support that L-type voltage-gated calcium channel agonists induce morphological changes at the ribbon synapse – in both the number of tethered vesicles and regarding the distribution of Ctbp2 puncta – shift swimming behavior and improve acoustic startle response.

Purpose: To report a case of pigmented paravenous retinochoroidal atrophy in a patient that was found to have an autosomal dominant pathogenic variant of the hexokinase 1 (HK1) gene. Methods: A case report. Results: A 41-year-old White woman with a distant family history of retinitis pigmentosa presented with a 5-year history of bilateral blurry and decreased vision that led to eventual loss of ability to drive. Color funduscopic photographs revealed retinochoroidal atrophy, hyper-reflective spots within the retina, and a paravenous distribution of pigment bilaterally. Given the patient's familial ocular history and workup, she was diagnosed with inherited retinal degeneration with phenotype suggestive of pigmented paravenous retinochoroidal atrophy. Genetic testing revealed a single rare variant, c.2551 G>A in the HK1 gene. Discussion: This case describes a pathogenic variant in HK1, a gene that has been associated with RP, but has not been previously reported in association with the pigmented paravenous retinochoroidal atrophy phenotype. This expands the phenotypes associated with HK1 pathogenic variant, p.Glu851Lys, and the genetic association of pigmented paravenous retinochoroidal atrophy to include HK1. Although pigmented paravenous retinochoroidal atrophy has been previously reported to be associated with CRB1 gene, no previous relationship to the HK1 gene has been described.

AbstractBranchio‐oto‐renal spectrum disorder (BORSD) is a rare autosomal dominant condition characterized by ear abnormalities with hard of hearing/deafness, second branchial arch malformations and renal anomalies. Pathogenic variations in EYA1 gene are found in the majority of clinically diagnosed individuals with BORSD. We describe an infant with BORSD related to a paternally inherited heterozygous pathogenic variation in EYA1 gene presenting with poor growth and hypoglycemia due to growth hormone deficiency. Magnetic resonance imaging revealed a diminutive pituitary gland and morphologically abnormal sella. Upon initiation of growth hormone therapy, the hypoglycemia resolved and catch up growth ensued. Pituitary abnormalities have not been reported previously in patients with BORSD. The zebrafish ortholog of eya1 is important for the development of adenohypophysis, suggesting that this patient's growth hormone deficiency and pituitary abnormality are part of BORSD. Inclusion of screening for pituitary hormone deficiency and pituitary imaging should be considered as a part of surveillance in patients with BORSD.

Purpose Hearing loss is a common impairment of the human senses with an estimated 48 million American adults reporting some trouble hearing; however, access to hearing health care is limited. Detection of hearing loss through a mobile, handheld tool can provide an important access point and potentially expedited access to the continuum of hearing health care. Here, we determined that GoAudio, a portable, automated hearing assessment tool, can be used to identify individuals who require additional hearing evaluation in a clinical workflow. Method This initial study included 24 adults, ages 18–65 years ( M = 50, SD = 12), tested with GoAudio versus “gold-standard” clinical audiometry for eight frequencies to evaluate “real-world” applications. Participants utilized noise-canceling headphones combined with a tablet-based application for the GoAudio assessment. Results The primary study outcome measurements were the comparison of hearing thresholds (dB HL) from clinical audiometry and GoAudio. Results suggest that GoAudio is comparable to clinical audiometry for the identification of hearing loss at most frequencies (except 1 kHz for both ears and 2 kHz in the right ear). Upon stratifying data based on age, we identified that GoAudio is capable of identifying suspected age-related hearing loss or hearing thresholds greater than 30 dB HL at higher frequencies in both ears. Conclusion The study results support that GoAudio can be used effectively in clinical practice workflows as a reliable hearing assessment tool for the identification of hearing loss at the majority of frequencies outside a sound-treated booth and can detect characteristics of age-related hearing loss. Supplemental Material https://doi.org/10.23641/asha.13087682

PurposeMore than 460 million people are impacted by disabling hearing loss worldwide. Hearing loss has negative impacts across the life span and varies by individual. Specifically, in children, hearing loss has been shown to affect learning outcomes, behavioral and cognitive growth, and psychosocial development. In adults, hearing loss has been shown to affect quality of life, social isolation, depression, and anxiety. The purpose of this review is to advance the understanding of the latest research in the development of new treatments of hearing loss, including gene therapy, stem cell therapy, and pharmacotherapies. We address the use of animals to model human hearing loss and the importance of animals in previous discoveries and developing new therapies. We highlight the importance of early identification for better speech and developmental outcomes specifically in pediatric individuals. Lastly, we review new possibilities in the prevention of hearing loss and the path to translation into practice.ConclusionsResearch and development of new therapies to treat hearing loss is an ever growing field with many notable successes. However, clinical translation still poses many challenges. Many discoveries related to gene therapy, stem cell therapy, and pharmacotherapy are in the early phases of clinical trials and hold promise. This review empowers audiologists to be aware of these most recent developments and be conscious of the evolving future landscape of treatment and management of hearing loss.