A mouse model for human hearing loss DFNB30 due to loss of function of myosin IIIA.

The motor protein myosin IIIA is critical for maintenance of normal hearing. Homozygosity and compound heterozygosity for loss-of-function mutations in MYO3A, which encodes myosin IIIA, are responsible for inherited human progressive hearing loss DFNB30. To further evaluate this hearing loss, we constructed a mouse model, Myo3a(KI/KI), that harbors the mutation equivalent to the nonsense allele responsible for the most severe human phenotype. Myo3a(KI/KI) mice were compared to their wild-type littermates. Myosin IIIA, with a unique N-terminal kinase domain and a C-terminal actin-binding domain, localizes to the tips of stereocilia in wild-type mice but is absent in the mutant. The phenotype of the Myo3a(KI/KI) mouse parallels the phenotype of human DFNB30. Hearing loss, as measured by auditory brainstem response, is reduced and progresses significantly with age. Vestibular function is normal. Outer hair cells of Myo3a(KI/KI) mice degenerate with age in a pattern consistent with their progressive hearing loss.

Profound, prelingual nonsyndromic deafness maps to chromosome 10q21 and is caused by a novel missense mutation in the Usher syndrome type IF gene PCDH15.

We studied a consanguineous family (Family A) from the island of Newfoundland with an autosomal recessive form of prelingual, profound, nonsyndromic sensorineural hearing loss. A genome-wide scan mapped the deafness trait to 10q21-22 (max LOD score of 4.0; D10S196) and fine mapping revealed a 16 Mb ancestral haplotype in deaf relatives. The PCDH15 gene was mapped within the critical region and was an interesting candidate because truncating mutations cause Usher syndrome type IF (USH1F) and two missense mutations have been previously associated with isolated deafness (DFNB23). Sequencing of the PCDH15 gene revealed 33 sequencing variants. Three of these variants were homozygous exclusively in deaf siblings but only one of them was not seen in ethnically matched controls. This novel c.1583 T>A transversion predicts an amino-acid substitution of a valine with an aspartic acid at codon 528 (V528D). Like the two DFNB23 mutations, the V528D mutation in Family A occurs in a highly conserved extracellular cadherin (EC) domain of PCDH15 and is predicted to be more deleterious than the previously identified DFNB23 missense mutations (R134G and G262D). Physical assessment, vestibular and visual function testing in deaf adults ruled out syndromic deafness because of Usher syndrome. This study validates the DFNB23 designation and supports the hypothesis that missense mutations in conserved motifs of PCDH15 cause nonsyndromic hearing loss. This emerging genotype-phenotype correlation in USH1F is similar to that in several other USH1 genes and cautions against a prognosis of a dual sensory loss in deaf children found to be homozygous for hypomorphic mutations at the USH1F locus.

An evidence-based review of cognitive and behavioral rehabilitation treatment studies in children with acquired brain injury.

OBJECTIVE: The aim of this study was to complete a systematic evidence-based review of published cognitive and behavioral treatment studies with pediatric subjects who have a history of an acquired brain injury (ABI). DATA SOURCES: We utilized PubMed and EMBASE to search peer-reviewed journals from 1980 to 2006. DATA SELECTION: Terms such as cognitive rehabilitation, speech therapy, language therapy, and behavior therapy were employed in the search and 28 studies met established criteria. DATA EXTRACTION: The data extracted from each study included specific details about the cognitive or behavioral treatment, subjects, study design, outcome measurements, and treatment effectiveness. DATA SYNTHESIS: The studies, involving 366 children and youth with ABI, were classified as 1 Class I study, 5 Class II studies, 6 Class III studies, and 16 Class IV studies. CONCLUSIONS: Despite a limited number of studies, 2 treatment recommendations and 1 option were developed from this systematic literature search.

A natural setting behavior management program for persons with acquired brain injury: a randomized controlled trial.

OBJECTIVE: To investigate the efficacy of a behavior management program delivered in the natural community setting for persons with brain injury and their caregivers. DESIGN: Three-group randomized controlled trial. SETTING: Homes and other community settings. PARTICIPANTS: Thirty-seven persons with traumatic and other acquired brain injury and their caregivers. INTERVENTIONS: Natural Setting Behavior Management (NSBM) involving education and individualized behavior modification program versus education only versus control group. MAIN OUTCOME MEASURES: Changes in frequency of targeted problematic behaviors. Subscale in Questionnaire on Resources and Stress, Maslach Burnout Inventory, and the Neurobehavioral Functioning Inventory. RESULTS: While no significant effects were detected at termination of education only (P<.075) or of NSBM (P<.56), significant treatment effects were found at the main outcome point 3 months after termination of services (P<.002). Rates of disruptive or aggressive behaviors declined significantly in the NSBM group. Differences in caregiver-rated stress, burden, and aggression were not statistically significant. CONCLUSIONS: A program of caregiver education and individualized behavior management in natural settings can decrease the frequency of disruptive behavioral challenges. Larger studies are needed to clarify the duration and intensity of education and individualized treatment required to diminish behavioral challenges and to understand relationships with general stress and burden experienced by caregivers.

Analysis of the role of the SA gene in blood pressure regulation by gene targeting.

The SA gene is expressed in the proximal tubule of the kidney and may be involved in blood pressure (BP) regulation. However, direct evidence for this is lacking. We constructed and analyzed an SA-null mouse in which exons 2 and 3 of the SA gene (including the start codon) had been deleted by homologous recombination. Basal BP and BP changes in response to increased salt and to treatment with losartan were compared between mice homozygous for the targeted SA allele (SA-/- mice) and littermates carrying the wild-type allele (SA+/+ mice). Molecular and biochemical analysis confirmed the lack of SA gene product in SA-/- mice. SA-/- mice grew normally, were fertile, and had no overt phenotype. With both indirect and direct techniques, basal BP was similar in SA-/- and SA+/+ mice. A high salt diet for 4 weeks caused a significant increase in BP in SA-/- and SA+/+, mice but there was no difference between the 2 strains. Losartan caused a significant decrease in BP, but again the response was similar between SA-/- and SA+/+ mice, as were their kidney renin mRNA levels. SA is not involved in the regulation of either basal or salt related BP, and the lack of differential effect in SA-/- mice is not a consequence of compensatory activation of the renin-angiotensin system.

From flies' eyes to our ears: mutations in a human class III myosin cause progressive nonsyndromic hearing loss DFNB30.

Normal vision in Drosophila requires NINAC, a class III myosin. Class III myosins are hybrid motor-signaling molecules, with an N-terminal kinase domain, highly conserved head and neck domains, and a class III-specific tail domain. In Drosophila rhabdomeres, NINAC interacts with actin filaments and with a PDZ scaffolding protein to organize the phototransduction machinery into a signaling complex. Recessive null mutations in Drosophila NINAC delay termination of the photoreceptor response and lead to progressive retinal degeneration. Here, we show that normal hearing in humans requires myosin IIIA, the human homolog of NINAC. In an extended Israeli family, nonsyndromic progressive hearing loss is caused by three different recessive, loss-of-function mutations in myosin IIIA. Of 18 affected relatives in Family N, 7 are homozygous and 11 are compound heterozygous for pairs of mutant alleles. Expression of mammalian myosin IIIA is highly restricted, with the strongest expression in retina and cochlea. The involvement of homologous class III myosins in both Drosophila vision and human hearing is an evolutionary link between these sensory systems.

The globular domain of the proalpha 1(I) N-propeptide is not required for secretion, processing by procollagen N-proteinase, or fibrillogenesis of type I collagen in mice.

The globular domain in the NH(2)-terminal propeptide (N-propeptide) of the proalpha1(I) chain is largely encoded by exon 2 of the Col1a1 gene and has been implicated in a number of processes that are involved in the biogenesis, maturation, and function of type I collagen. These include intracellular chain association, transcellular transport and secretion, proteolytic processing of the precursor, feedback regulation of synthesis, and control of fibrillogenesis. However, none of these proposed functions has been firmly established. To evaluate the function of this procollagen domain we have used a targeted mutagenesis approach to generate mice that lack exon 2 in the Col1a1 gene. Mouse lines were established on both a mixed 129 OlaHsd/Sv and C57BL/6 background and a pure 129 OlaHsd/Sv background. Adult mice on the mixed background are normal in appearance and are fertile. To the extent that they have been studied, procollagen synthesis, secretion, and proteolytic processing are normal in these mice, and collagen fibrillogenesis is only slightly altered. However, breeding of heterozygous mutant mice on the 129 background generated homozygous mutants at only 64% of the expected frequency. These findings suggest that although the N-propeptide is not essential for collagen biogenesis in mice it may play some essential role during embryonic development.