Mutations in a plasma membrane Ca2+-ATPase gene cause deafness in deafwaddler mice.

Hearing loss is the most common sensory deficit in humans. Because the auditory systems of mice and humans are conserved, studies on mouse models have predicted several human deafness genes and identified new genes involved in hearing. The deafwaddler (dfw) mouse mutant is deaf and displays vestibular/motor imbalance. Here we report that the gene encoding a plasma membrane Ca2+-ATPase type 2 pump (Atp2b2, also known as Pmca2) is mutated in dfw. An A-->G nucleotide transition in dfw DNA causes a glycine-to-serine substitution at a highly conserved amino-acid position, whereas in a second allele, dfw2J, a 2-base-pair deletion causes a frameshift that predicts a truncated protein. In the cochlea, the protein Atp2b2 is localized to stereocilia and the basolateral wall of hair cells in wild-type mice, but is not detected in dfw2J mice. This indicates that mutation of Atp2b2 may cause deafness and imbalance by affecting sensory transduction in stereocilia as well as neurotransmitter release from the basolateral membrane. These mutations affecting Atp2b2 in dfw and dfw2J are the first to be found in a mammalian plasma membrane calcium pump and define a new class of deafness genes that directly affect hair-cell physiology.

Mutant beta-spectrin 4 causes auditory and motor neuropathies in quivering mice.

The autosomal recessive mouse mutation quivering (qv), which arose spontaneously in 1953, produces progressive ataxia with hind limb paralysis, deafness and tremor. Six additional spontaneous alleles, qvJ, qv2J, qv3J, qv4J, qvlnd and qvlnd2J, have been identified. Ear twitch responses (Preyer's reflex) to sound are absent in homozygous qv/qv mice, although cochlear morphology seems normal and cochlear potentials recorded at the round window are no different from those of control mice. However, responses from brainstem auditory nuclei show abnormal transmission of auditory information, indicating that, in contrast to the many known mutations causing deafness originating in the cochlea, deafness in qv is central in origin. Here we report that quivering mice carry loss-of-function mutations in the mouse beta-spectrin 4 gene (Spnb4) that cause alterations in ion channel localization in myelinated nerves; this provides a rationale for the auditory and motor neuropathies of these mice.

The natural history of early recurrent carotid artery stenosis.

BACKGROUND: Early recurrent carotid stenosis, defined as greater than 50% stenosis within 2 years of a carotid endarterectomy (CEA), occurs in 4% to 19% of patients. These lesions are secondary to myointimal hyperplasia (MH). The natural history of these lesions has been examined prospectively, but the appropriate management of these lesions has not been clearly defined. The vascular surgery service at Madigan Army Medical Center (MAMC) has prospectively collected a cohort of patients with recurrent high-grade carotid stenoses following CEA to determine their natural history and define the ideal therapeutic approach for those lesions. METHODS: Patients undergoing CEA between January 1, 1993, and January 1, 1997, at a single tertiary care institution were followed prospectively with postoperative carotid duplexes at 3-month intervals for the first year and then every 6 months for a year and then annually thereafter. Data were collected regarding patient demographics, type of carotid closure, neurologic morbidity, and death. These results were compared with accepted rates in the literature. Discrete variables were tested for significance by chi-square analysis and Fisher's exact test. A P value less than or equal to 0.05 was considered significant. RESULTS: One hundred and seventy-four (174) patients with 181 operative sites were evaluated. Fourteen patients with 17 sites (9%) had recurrent stenosis. Twelve patients with 14 sites (7%) had stenoses of 50% to 79%. All were asymptomatic. Two patients with 3 sites (2%) had stenoses greater than 80%. Two sites were managed operatively because of neurologic symptoms or preocclusive nature and one remains asymptomatic and stable on serial duplex imaging. All lesions were present at 6 months and those in the 50% to 79% category did not progress in follow-up. Recurrent carotid stenosis occurred to a significantly higher degree in women (women 11 of 60 18.3% versus men 6 of 114 5.3%; P = 0.25), primary closure versus patch angioplasty (primary 6 of 22 27.3% versus patch 11 of 159 6.9%; P = 0.01), and dacron versus polytetrafluoroethylene (PTFE) patch angioplasty (dacron 7 of 36 19.4% versus PTFE 2 of 100 2.0%; P = 0.02). CONCLUSION: Early recurrent stenosis (50% to 79%) is a benign lesion. Patch angioplasty is preferred over primary closure. Dacron patches had a significantly higher rate of recurrent stenosis when compared with PTFE patches. Women undergoing CEA are more prone to recurrent stenosis. Postoperative duplex at 3 and 6 months will identify recurrent carotid stenosis (given a normal duplex prior to discharge following CEA). Moderate high-grade (50% to 79%) stenoses are benign. High-grade (80% to 99%) stenoses require individual management.

Physical and genetic maps of the deafwaddler region on distal mouse Chr 6.

The deafwaddler (dfw) mutation, displaying motor ataxia and profound deafness, arose spontaneously in a C3H/HeJ colony and was mapped previously to distal mouse Chr 6. In this study, a high-resolution genetic map was generated by positioning 10 microsatellite markers and 5 known genes on a 968-meioses intersubspecific backcross segregating for dfw [(CAST/Ei(-)+/+ x C3HeB/ FeJ-dfw/dfw) x C3HeB/FeJ-dfw/dfw], giving the following marker order and sex-averaged distances: D6Mit64-(0.10 + 0.10 cM)-Pang-(1.24 + 0.36 cM)-Itpr1-(0.62 + 0.25 cM)-D6Mit108-(0.52 + 0.23 cM)-D6Mit54-(0.21 + 0.15 cM)-D6Mit23, D6Mit107, D6Mit328-(0.72 + 0.27 cM)-D6Mit11-(0.21 + 0.15 cM)-dfw-(0.93 + 0.31 cM)-Gat4, D6Mit55-(0.10 + 0.10 cM)-D6Mit63-(0.31 + 0.18 cM)-Syn2-(0.62 + 0.25 cM)-D6Mit44 (Rho). Female and male genetic maps are similar immediately surrounding the dfw locus, but show marked differences in other areas. A yeast artificial chromosome-based physical map suggests that the closest markers flanking the dfw locus, D6Mit11 (proximal) and Gat4, D6Mit55 (distal), are contained within 650-950 kb. The human homologues of the flanking loci Itpr1 (proximal) and Syn2 (distal) map to chromosome 3p25-p26, suggesting that the human homologue of the dfw gene is located within this same region.

Physical and comparative mapping of distal mouse chromosome 16. 5 p5.

Distal mouse Chromosome 16 (Chr. 16) includes a region of conserved linkage with human Chromosome 21 (Chr. 21). Mouse models of Down syndrome based on trisomy of distal Chr. 16 have several phenotypes similar to those seen in human patients and have proven useful for correlating dosage imbalance of specific genes with specific developmental anomalies. The degree to which such findings can be related to Down syndrome depends on how well the conserved synteny is maintained. Twenty-four genes have been mapped in both species and there are no discordancies, but the region could carry hundreds of genes. Comparative sequence represents the ultimate comparative map and will aid in identification of genes and their regulatory sequences. A physical map of the distal 4.5 Mb of Chr. 16 has been assembled as an essential step toward a map of sequence-ready templates. The map consists of 51 YACs and 15 BACs and includes 18 transcripts, 9 of which are mapped for the first time in mouse, and 3 of which are, for the first time, described in either species. YAC fragmentation was used to precisely localize the 49 markers on the map. Comparison of this physical map with that of the corresponding region on Chr. 21 shows conservation not only of gene order but of size in the 3 Mb from Cbr1 to Ets2; distal to Ets2, the human map is expanded.