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H G Lidov

Publications and source records attributed to H G Lidov.

At least 19 recordsLinked to original sources
PubMed2001

Desmuslin, an intermediate filament protein that interacts with alpha -dystrobrevin and desmin.

Dystrobrevin is a component of the dystrophin-associated protein complex and has been shown to interact directly with dystrophin, alpha1-syntrophin, and the sarcoglycan complex. The precise role of alpha-dystrobrevin in skeletal muscle has not yet been determined. To study alpha-dystrobrevin's function in skeletal muscle, we used the yeast two-hybrid approach to look for interacting proteins. Three overlapping clones were identified that encoded an intermediate filament protein we subsequently named desmuslin (DMN). Sequence analysis revealed that DMN has a short N-terminal domain, a conserved rod domain, and a long C-terminal domain, all common features of type 6 intermediate filament proteins. A positive interaction between DMN and alpha-dystrobrevin was confirmed with an in vitro coimmunoprecipitation assay. By Northern blot analysis, we find that DMN is expressed mainly in heart and skeletal muscle, although there is some expression in brain. Western blotting detected a 160-kDa protein in heart and skeletal muscle. Immunofluorescent microscopy localizes DMN in a stripe-like pattern in longitudinal sections and in a mosaic pattern in cross sections of skeletal muscle. Electron microscopic analysis shows DMN colocalized with desmin at the Z-lines. Subsequent coimmunoprecipitation experiments confirmed an interaction with desmin. Our findings suggest that DMN may serve as a direct linkage between the extracellular matrix and the Z-discs (through plectin) and may play an important role in maintaining muscle cell integrity.

Amino Acid Sequence↗
PubMed2001

Prediction of safe duration of hypothermic circulatory arrest by near-infrared spectroscopy.

OBJECTIVE: Hypothermic circulatory arrest is widely used for adults with aortic arch disease as well as for children with congenital heart disease. At present, no method exists for monitoring safe duration of circulatory arrest. Near-infrared spectroscopy is a new technique for noninvasive monitoring of cerebral oxygenation and energy state. In the current study, the relationship between near-infrared spectroscopy data and neurologic outcome was evaluated in a survival piglet model with hypothermic circulatory arrest. METHODS: Thirty-six piglets (9.36 +/- 0.16 kg) underwent circulatory arrest under varying conditions with continuous monitoring by near-infrared spectroscopy (temperature 15 degrees C or 25 degrees C, hematocrit value 20% or 30%, circulatory arrest time 60, 80, or 100 minutes). Each setting included 3 animals. Neurologic recovery was evaluated daily by neurologic deficit score and overall performance category. Brain was fixed in situ on postoperative day 4 and examined by histologic score. RESULTS: Oxygenated hemoglobin signal declined to a plateau (nadir) during circulatory arrest. Time to nadir was significantly shorter with lower hematocrit value (P <.001) and higher temperature (P <.01). Duration from reaching nadir until reperfusion ("oxygenated hemoglobin signal nadir time") was significantly related to histologic score (r (s) = 0.826), neurologic deficit score (r (s) = 0.717 on postoperative day 1; 0.716 on postoperative day 4), and overall performance category (r (s) = 0.642 on postoperative day 1; 0.702 on postoperative day 4) (P <.001). All animals in which oxygenated hemoglobin signal nadir time was less than 25 minutes were free of behavioral or histologic evidence of brain injury. CONCLUSION: Oxygenated hemoglobin signal nadir time determined by near-infrared spectroscopy monitoring is a useful predictor of safe duration of circulatory arrest. Safe duration of hypothermic circulatory arrest is strongly influenced by perfusate hematocrit value and temperature during circulatory arrest.

Analysis of Variance↗
PubMed2000

Filamin 2 (FLN2): A muscle-specific sarcoglycan interacting protein.

Mutations in genes encoding for the sarcoglycans, a subset of proteins within the dystrophin-glycoprotein complex, produce a limb-girdle muscular dystrophy phenotype; however, the precise role of this group of proteins in the skeletal muscle is not known. To understand the role of the sarcoglycan complex, we looked for sarcoglycan interacting proteins with the hope of finding novel members of the dystrophin-glycoprotein complex. Using the yeast two-hybrid method, we have identified a skeletal muscle-specific form of filamin, which we term filamin 2 (FLN2), as a gamma- and delta-sarcoglycan interacting protein. In addition, we demonstrate that FLN2 protein localization in limb-girdle muscular dystrophy and Duchenne muscular dystrophy patients and mice is altered when compared with unaffected individuals. Previous studies of filamin family members have determined that these proteins are involved in actin reorganization and signal transduction cascades associated with cell migration, adhesion, differentiation, force transduction, and survival. Specifically, filamin proteins have been found essential in maintaining membrane integrity during force application. The finding that FLN2 interacts with the sarcoglycans introduces new implications for the pathogenesis of muscular dystrophy.

Amino Acid Sequence↗
PubMed1999

Oxygenation strategy and neurologic damage after deep hypothermic circulatory arrest. II. hypoxic versus free radical injury.

OBJECTIVES: Laboratory studies suggest that myocardial reperfusion injury is exacerbated by free radicals when pure oxygen is used during cardiopulmonary bypass. In phase I of this study we demonstrated that normoxic perfusion during cardiopulmonary bypass does not increase the risk of microembolic brain injury so long as a membrane oxygenator with an arterial filter is used. In phase II of this study we studied the hypothesis that normoxic perfusion increases the risk of hypoxic brain injury after deep hypothermia with circulatory arrest. METHODS: With membrane oxygenators with arterial filters, 10 piglets (8-10 kg) underwent 120 minutes of deep hypothermia and circulatory arrest at 15 degrees C, were rewarmed to 37 degrees C, and were weaned from bypass. In 5 piglets normoxia (PaO2 64-181 mm Hg) was used during cardiopulmonary bypass and in 5 hyperoxia (PaO2 400-900 mm Hg) was used. After 6 hours of reperfusion the brain was fixed for histologic evaluation. Near-infrared spectroscopy was used to monitor cerebral oxyhemoglobin and oxidized cytochrome a,a3 concentrations. RESULTS: Histologic examination revealed a significant increase in brain damage in the normoxia group (score 12.4 versus 8.6, P =.01), especially in the neocortex and hippocampal regions. Cytochrome a,a 3 and oxyhemoglobin concentrations tended to be lower during deep hypothermia and circulatory arrest in the normoxia group (P =.16). CONCLUSIONS: In the setting of prolonged deep hypothermia and circulatory arrest with membrane oxygenators, normoxic cardiopulmonary bypass significantly increases histologically graded brain damage with respect to hyperoxic cardiopulmonary bypass. Near-infrared spectroscopy suggests that the mechanism is hypoxic injury, which presumably overwhelms any injury caused by increased oxygen free radicals.

Animals↗
PubMed1999

A novel sialyl Lewis X analog attenuates cerebral injury after deep hypothermic circulatory arrest.

BACKGROUND: The initial step in the inflammatory process, which can be initiated by cardiopulmonary bypass and by ischemia/reperfusion, is mediated by interactions between selectins on endothelial cells and on neutrophils. We studied the effects of selectin blockade using a novel Sialyl Lewis X analog (CY-1503) on recovery after deep hypothermic circulatory arrest in a piglet model. METHODS: Twelve Yorkshire piglets were subjected to cardiopulmonary bypass, 30 minutes of cooling, 100 minutes of circulatory arrest at 15 degrees C, and 40 minutes of rewarming. Five animals received a bolus of 60 mg/kg of CY-1503 and an infusion (3 mg/kg per hour) for 24 hours from reperfusion (group O), and 7 randomly selected control piglets received saline solution (group C). Body weight and total body water content were evaluated 3 hours and 24 hours after reperfusion by a bio-impedance technique. Neurologic recovery of animals was evaluated daily by neurologic deficit score (0 = normal, 500 = brain death) and overall performance categories (1 = normal, 5 = brain death). The brain was fixed in situ on the fourth postoperative day and examined by histologic score (0 = normal, 5+ = necrosis) in a blinded fashion. RESULTS: Two of 7 animals in group C died. The neurologic deficit score was significantly lower in group O than in group C (postoperative day 1, P <.001; postoperative day 2, P =.02). The overall performance category was significantly lower in group O than in group C on postoperative day 2 (P =.01). Percentage total body water after cardiopulmonary bypass was significantly higher in group C than in group O (P =.03). Histologic score tended to be higher in group C than in group O, but this difference did not reach statistical significance (group O = 0.5 +/- 0.7; group C = 1.3 +/- 1.off CONCLUSION: Blockade of selectin adhesion molecules by saturation with a Sialyl Lewisx analog accelerates recovery after 100 minutes of deep hypothermic circulatory arrest in a piglet survival model.

Animals↗
PubMed1999

Gangliocytoma masquerading as a prolactinoma. Case report.

The authors describe the case of a 36-year-old man who presented with bitemporal hemianopsia and a serum prolactin concentration of 1440 ng/ml. Magnetic resonance imaging of the pituitary revealed a presumed macroadenoma with suprasellar and temporal lobe extension. Although the patient's prolactin level was lowered to 55 ng/ml by bromocriptine therapy, no tumor shrinkage occurred. Fourteen months later, progression of visual field defects necessitated transsphenoidal resection, which was incomplete. Immunocytochemical analysis of the biopsy tissue was positive for prolactin and, in view of the clinical picture, more detailed analysis was not performed. External-beam radiotherapy was given 2 years later because of enlargement of residual tumor. Subsequently, despite a fall in the serum prolactin concentration to less than 20 ng/ml in response to the course of bromocriptine, the mass displayed further extension into the temporal lobe. Nine years after the patient's initial presentation, he underwent transfrontal craniotomy for sudden deterioration in visual acuity caused by hemorrhage into the mass. No adenohypophyseal tissue was identified in the resected tissue. The mass was composed of dysplastic neurons that were strongly immunoreactive for synaptophysin and neurofilament (indicating neural differentiation) and prolactin. Review of the original biopsy specimen indicated that the prolactin-positive cells had striking neuronal morphological characteristics. The final diagnosis in this case is prolactin-secreting gangliocytoma. Although exceedingly rare, this disease must be added to the differential diagnosis in cases of "prolactinoma" when bromocriptine therapy is followed by a marked decline in serum prolactin that is not accompanied by significant tumor shrinkage. Furthermore, in such instances, consideration should be given to "obtaining a biopsy sample prior to electing for radiotherapy.

Adult↗
PubMed1998

Molecular organization of sarcoglycan complex in mouse myotubes in culture.

The sarcoglycans are a complex of four transmembrane proteins (alpha, beta, gamma, and delta) which are primarily expressed in skeletal muscle and are closely associated with dystrophin and the dystroglycans in the muscle membrane. Mutations in the sarcoglycans are responsible for four autosomal recessive forms of muscular dystrophy. The function and the organization of the sarcoglycan complex are unknown. We have used coimmunoprecipitation and in vivo cross-linking techniques to analyze the sarcoglycan complex in cultured mouse myotubes. We demonstrate that the interaction between beta- and delta-sarcoglycan is resistant to high concentrations of SDS and alpha-sarcoglycan is less tightly associated with other members of the complex. Cross-linking experiments show that beta-, gamma-, and delta-sarcoglycan are in close proximity to one another and that delta-sarcoglycan can be cross-linked to the dystroglycan complex. In addition, three of the sarcoglycans (beta, gamma, and delta) are shown to form intramolecular disulfide bonds. These studies further our knowledge of the structure of the sarcoglycan complex. Our proposed model of their interactions helps to explain some of the emerging data on the consequences of mutations in the individual sarcoglycans, their effect on the complex, and potentially the clinical course of muscular dystrophies.

Amino Acid Sequence↗
PubMed1998

Effects of oncotic pressure and hematocrit on outcome after hypothermic circulatory arrest.

BACKGROUND: A recent study found that a higher-perfusate hematocrit was associated with improved neurologic recovery after deep hypothermic circulatory arrest. The current study examined the relative contributions of oxygen delivery and colloid oncotic pressure to this result, as well as the efficacy of different colloidal agents and modified ultrafiltration. METHODS: Twenty-six piglets were randomized into five groups (n = 5 or 6 animals per group): control group 1--blood and crystalloid prime, hematocrit of 20%; group 2--blood and hetastarch prime, hematocrit of 20%; group 3--blood and pentafraction prime, hematocrit of 20%; group 4--blood and crystalloid prime with 10 minutes of modified ultrafiltration; group 5--whole blood prime, hematocrit of 30%. All groups underwent 60 minutes of deep hypothermic circulatory arrest at 15 degrees C. RESULTS: Groups 2 and 3 showed less body weight gain (analysis of variance, p = 0.001; group 2 versus group 1, p = 0.0009; group 3 versus group 1, p = 0.0009) and body water content after cardiopulmonary bypass (analysis of variance, p = 0.001; group 2 versus group 1, p = 0.003; group 3 versus group 1, p = 0.013). Group 5 showed more rapid recovery of phosphocreatine and intracellular acidosis, as measured by magnetic resonance spectroscopy, during rewarming than group 1 did (phosphocreatine, p = 0.0329; intracellular acidosis, p = 0.0462). Group 3 also showed accelerated recovery of intracellular acidosis (p = 0.0411). Cytochrome a,a3 recovery, determined by near-infrared spectroscopy, was significantly better in group 5 than in group 1 and worse in group 2 than in group 1 after rewarming. The neurologic deficit score and overall performance category score were best in group 5 (neurologic deficit score, p = 0.012; overall performance category score, p = 0.046) on the first postoperative day. Group 3 also had a better overall performance category score than group 1 did (p = 0.0068). Only group 1 and 2 animals showed histologic damage. CONCLUSIONS: Both higher hematocrit and higher colloid oncotic pressure with pentafraction improve cerebral recovery after deep hypothermic circulatory arrest. The higher hematocrit improves cerebral oxygen delivery but does not reduce total body edema. Modified ultrafiltration after cardiopulmonary bypass is less effective than having a higher initial prime hematocrit or colloid oncotic pressure.

Animals↗
PubMed1998

Postischemic hyperthermia exacerbates neurologic injury after deep hypothermic circulatory arrest.

BACKGROUND: Aggressive surface warming is a common practice in the pediatric intensive care unit. However, recent rodent data emphasize the protective effect of mild (2 degrees - 3 degrees C) hypothermia after cerebral ischemia. This study evaluates different temperature regulation strategies after deep hypothermic circulatory arrest with a survival piglet model. METHODS: Fifteen piglets were randomly assigned to 3 groups. All groups underwent 100 minutes of deep hypothermic circulatory arrest at 15 degrees C. Brain temperature was maintained at 34 degrees C for 24 hours after cardiopulmonary bypass in group I, 37 degrees C in group II, and 40 degrees C in group III. Neurobehavioral recovery was evaluated daily for 3 days after extubation by neurologic deficit score (0, normal; 500, brain death) and overall performance category (1, normal; 5, brain death). Histologic examination was assessed for hypoxic-ischemic injury (0, normal; 5, necrosis) in a blinded fashion. RESULTS: All results are expressed as mean +/- standard deviation. Recovery of neurologic deficit score (12.0 +/- 17.8, 47.0 +/- 49.95, 191.0 +/- 179.83; P = .05 for group I vs III), overall performance category (1.0 +/- 0.0, 1.4 +/- 0.6, 2.8 +/- 1.3; P < .05 for group I vs III), and histologic scores (0.0 +/- 0.0, 1.0 +/- 1.2, 2.8 +/- 1.8; P < .05 for group I vs III cortex) were significantly worse in hyperthermic group III. These findings were associated with a significantly lower cytochrome aa3 recovery determined by near-infrared spectroscopy in group III animals (P = .0041 for group I vs III). No animal recovered to baseline electroencephalographic value by 48 hours after deep hypothermic circulatory arrest. Recovery was significantly delayed in the hyperthermic group III animals, with a lower amplitude 14 hours after the operation, which gradually increased with time (P < .05 for group III vs groups I and II). CONCLUSIONS: Mild postischemic hyperthermia significantly exacerbates functional and structural neurologic injury after deep hypothermic circulatory arrest and should therefore be avoided.

Animals↗
PubMed1998

Caveolin-3 in muscular dystrophy.

The dystrophin-glycoprotein complex (DGC) serves as a link between cytoplasmic actin, the membrane and the extracellular matrix of striated muscle. Genetic defects in genes encoding a subset of DGC proteins result in muscular dystrophy and a secondary decrease in other DGC proteins. Caveolae are dynamic structures that have been implicated in a number of functions including endocytosis, potocytosis and signal transduction. Caveolin (VIP-21) is thought to play a structural role in the formation of non-clathrin-coated vesicles in a number of different cell types. Caveolin-3, or M-caveolin, was identified as a muscle-specific form of the caveolin family. We show that caveolin-3 co-purifies with dystrophin, and that a fraction of caveolin-3 is a dystrophin-associated protein. We isolated the gene for human caveolin-3 and mapped it to chromosome 3p25. We determined the genomic organization of human caveolin-3 and devised a screening strategy to look for mutations in caveolin-3 in patients with muscular dystrophy. Of 82 patients screened, two nucleotide changes were found that resulted in amino acid substitutions (G55S and C71W); these changes were not seen in a control population. The amino acid changes map to a functionally important domain in caveolin-3, suggesting that these are not benign polymorphisms and instead are disease-causing mutations.

Amino Acid Sequence↗
PubMed1998

Dystrophin and Dp140 in the adult rodent kidney.

Full-length dystrophin and a truncated carboxy-terminal isoform, Dp140, also encoded by the dystrophin gene, are expressed in rodent kidney. Dystrophin is localized to the vascular smooth muscle and mesangial cells. Dp140 was initially identified in the brain as well as kidney. In kidney, Dp140 is localized to the basal surface of tubule epithelial cells. Morphology and double-labeling suggest that it is restricted to the ascending loop of Henle, distal convoluted tubule, and proximal end of the collecting ducts. Because both dystrophin and Dp140 contain the same carboxy-terminal domain--which in skeletal muscle forms a link to integral membrane proteins and in turn to the extracellular matrix--Dp140 in the tubule epithelium might contribute to anchoring the basal aspect of the cells to the basement membrane. The identification of dystrophin gene products in kidney parenchyma also raises the possibility of subtle renal abnormalities, not previously suspected, as part of the Duchenne muscular dystrophy phenotype.

Animals↗
PubMed1997

Dp140: alternatively spliced isoforms in brain and kidney.

Dp140, a protein composed of the distal rod domain and carboxy-terminal domain of dystrophin, is expressed only in brain and kidney; transcription is initiated at a unique first exon located in dystrophin intron 44. Both tissues express specific isoforms with distinct alternative splicing of exons 71-74 and 78. The carboxy-terminal domain of Dp140 is identical to that of full-length 427-kDa dystrophin, and it is this region that is associated, with the "dystrophin-associated protein" complex in skeletal muscle. Alternative splicing encodes domains that have been shown to be protein-binding regions; thus this alternative splicing may regulate the association of Dp140 with integral membrane proteins. The 5' flanking region of genomic DNA adjacent to the Dp140 first exon contains a variety of transcription factor-binding motifs, some of which could regulate neuroglial-specific gene expression.

Alternative Splicing↗
PubMed1997

Molecular characterization of Br-cadherin, a developmentally regulated, brain-specific cadherin.

Cadherins are a family of transmembrane proteins that play a crucial role in cell adhesion and in morphogenesis. Several of the cadherins are expressed in the nervous system, but none is neuron-specific. We characterize a new member of the cadherin family, Br-cadherin, which is present exclusively in the central nervous system. Although the Br-cadherin protein is confined to the central nervous system, its mRNA is present in several additional tissues, suggesting that there is posttranscriptional control of this gene's expression. Within the central nervous system, Br-cadherin appears to be expressed specifically by neurons. In the mouse, its expression becomes detectable during the first postnatal week, which corresponds temporally to the onset of synaptogenesis and dendrite outgrowth in the brain. This pattern of expression is consistent with a role for Br-cadherin in neuronal development, perhaps specifically with synaptogenesis.

Aging↗
PubMed1996

Intermittent whole-body perfusion with "somatoplegia' versus blood perfusate to extend duration of circulatory arrest.

BACKGROUND: Continuous whole-body perfusion for > 3 hours with a cold asanguineous blood substitute, hypothermosol (HTS) solution, has been reported to preserve organ function. We used this solution in a survival animal model to evaluate its possible application in extending the safe duration of deep hypothermic circulatory arrest (DHCA). METHODS AND RESULTS: Fifteen piglets were placed on cardiopulmonary bypass (CPB), were cooled to a nasopharyngeal temperature of 15 degrees C, and underwent 100 minutes of DHCA. Control animals (group C, n = 5) had uninterrupted DHCA, group HTS animals were perfused with maintenance HTS for 5 minutes every 25 minutes during DHCA (n = 5), and group B animals were intermittently perfused as for group HTS with the blood in the bypass circuit (n = 5). Cerebral oxygenation was assessed with near-infrared spectroscopy throughout CPB and DHCA. Animals were allowed to recover after CPB and underwent daily neurobehavioral evaluation by the neurological deficit score (NDS: 0, normal; 500, brain death) and overall performance categories (OPC: 1, normal; 5, brain death). Blood samples were drawn on postoperative day (POD) 1 for selected biochemistry analysis. On POD 4, the brain of each animal was perfusion-fixed for histological evaluation, and a neurohistological score (NHS: 0, normal; 5+, necrosis) was assigned for the degree of neuronal injury. All animals except one from group HTS survived surgery. Mean perfusion pressures were significantly elevated in group B compared with group C and group HTS during the rewarming phase (P < .05). The HbO2 signal increased in all groups during the cooling phase of CPB and remained significantly above baseline only in group B during DHCA (P < .05). SGOT, LDH, ALP, and CPK levels on POD 1 were elevated above baseline in all groups. The increase in SGOT and ALP was significantly greater in group HTS than in the other groups (P < .02). The NDS was lower in group B on each postoperative evaluation, being significant relative to group C and group HTS on POD 1 (P < .05) and significantly lower than group C on POD 2 (P < .05). The OPC score was significantly lower in group B than in group C and group HTS on POD 2 (P < .05) and significantly lower than in group C on PODs 3 and 4 (P < .05). The NHS was lower in group B than in the other 2 groups, being significant relative to group C in the neocortex (P < .007). CONCLUSIONS: Intermittent whole-body asanguineous perfusion with hypothermosol solution does not extend cerebral protection in a porcine survivor model of DHCA. Neurobehavioral and histological outcomes are improved in animals receiving intermittent blood perfusion during prolonged DHCA.

Animals↗
PubMed1996

Higher hematocrit improves cerebral outcome after deep hypothermic circulatory arrest.

BACKGROUND: Various degrees of hemodilution are currently in clinical use during deep hypothermic circulatory arrest to counteract deleterious rheologic effects linked with brain injury by previous reports. MATERIAL AND METHODS: Seventeen piglets were randomly assigned to three groups. Group I piglets (n = 7) received colloid and crystalloid prime (hematocrit < 10%), group II piglets (n = 5) received blood and crystalloid prime (hematocrit 20%), group III piglets (n = 5) received blood prime (hematocrit 30%). All groups underwent 60 minutes of deep hypothermic circulatory arrest at 15 degrees C with continuous magnetic resonance spectroscopy and near-infrared spectroscopy Neurologic recovery was evaluated for 4 days (neurologic deficit score 0, normal, to 500, brain death; overall performance category 1, normal, to 5, brain death). Neurohistologic score (0, normal, to 5+, necrosis) was assessed after the animals were euthanized on day 4. RESULTS: Group I had significant loss of phosphocreatine and intracellular acidosis during early cooling (phosphocreatine in group I, 86.3% +/- 26.8%; group II, 117.3% +/- 8.6%; group III, 110.9% +/- 2.68%; p = 0.0008; intracellular pH in group I, 6.95 +/- 0.18; group II, 7.28 +/- 0.04; group III, 7.49 +/- 0.04; p = 0.0048). Final recovery was the same for all groups. Cytochrome aa3 was more reduced in group I during deep hypothermic circulatory arrest than in either of the other groups (group I, -43.6 +/- 2.6; group II, -16.0 +/- 5.2; group III, 1.3 +/= 3.1; p < 0.0001). Neurologic deficit score was best preserved in group III (p < 0.05 group II vs group III) on the first postoperative day, although this difference diminished with time and all animals were neurologically normal after 4 days. Histologic assessment was worst among group I in neocortex area (group I, 1.33 +/- 0.3; group II, 0.22 +/- 0.1; group III, 0.40 +/- 0.2, p < 0.05, group I vs group II; p = 0.0287, group I vs group III). CONCLUSION: Extreme hemodilution during cardiopulmonary bypass may cause inadequate oxygen delivery during early cooling. The higher hematocrit with a blood prime is associated with improved cerebral recovery after deep hypothermic circulatory arrest.

Adenosine Triphosphate↗
PubMed1996

Mutations that disrupt the carboxyl-terminus of gamma-sarcoglycan cause muscular dystrophy.

Recently, mutations in the genes encoding several of the dystrophin-associated proteins have been identified that produce phenotypes ranging from severe Duchenne-like autosomal recessive muscular dystrophy to the milder limb-girdle muscular dystrophies (LGMDs). LGMD type 2C is generally associated with a more severe clinical course and is prevalent in northern Africa. A previous study identified a single base pair deletion in the gene encoding the dystrophin-associated protein gamma-sarcoglycan in a number of Tunisian muscular dystrophy patients. To investigate whether gamma-sarcoglycan gene mutations cause autosomal recessive muscular dystrophy in other populations, we studied 50 muscular dystrophy patients from the United States and Italy. The muscle biopsies from these 50 patients showed no abnormality of dystrophin but did show diminished immunostaining for the dystrophin-associated protein alpha-sarcoglycan. Four patients with a severe muscular dystrophy phenotype were identified with homozygous, frameshifting mutations in gamma-sarcoglycan. Two of the four have microdeletions that disrupt the distal carboxyl-terminus of gamma-sarcoglycan yet result in a complete absence of gamma-and beta-sarcoglycan suggesting the importance of this region for stability of the sarcoglycan complex. This region of gamma-sarcoglycan, like beta-sarcoglycan, has a number of cysteine residues similar to those in epidermal growth factor cysteine-rich regions.

Amino Acid Sequence↗