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M Zatz

Publications and source records attributed to M Zatz.

At least 19 recordsLinked to original sources
PubMed2006

Mutation analysis in the FKRP gene provides an explanation for a rare cause of intrafamilial clinical variability in LGMD2I.

We report a limb-girdle muscular dystrophy 2I family with three affected sisters and a highly variable clinical course. FKRP gene sequencing showed that all three sisters carried a nonsense paternal mutation (W225X). The two oldest sisters with a severe phenotype carried two maternal mutations V79M and P89A. However, the youngest sister with a milder course carried the paternal and only the V79M maternal mutation, due to an intragenic recombination.

Adolescent↗
PubMed2005

A family with McLeod syndrome and calpainopathy with clinically overlapping diseases.

The authors describe a family with six patients with muscular dystrophy with a variable course. One is a compound heterozygote for CAPN3 mutations (calpainopathy) and the others have a single CAPN3 mutation. Linkage analysis and sequencing revealed a XK gene mutation (McLeod syndrome). This illustrates the variable phenotype of XK mutations and suggests the possibility that CAPN3 heterozygotes may have their condition caused by nonallelic mutations in other unrelated genes.

Adolescent↗
PubMed2005

Molecular cloning, localization and circadian expression of chicken melanopsin (Opn4): differential regulation of expression in pineal and retinal cell types.

The avian retina and pineal gland contain autonomous circadian oscillators and photo-entrainment pathways, but the photopigment(s) that mediate entrainment have not been definitively identified. Melanopsin (Opn4) is a novel opsin involved in entrainment of circadian rhythms in mammals. Here, we report the cDNA cloning of chicken melanopsin and show its expression in retina, brain and pineal gland. Like the melanopsins identified in amphibians and mammals, chicken melanopsin is more similar to the invertebrate retinaldehyde-based photopigments than the retinaldehyde-based photopigments typically found in vertebrates. In retina, melanopsin mRNA is expressed in cells of all retinal layers. In pineal gland, expression was strong throughout the parenchyma of the gland. In brain, expression was observed in a few discrete nuclei, including the lateral septal area and medial preoptic nucleus. The retina and pineal gland showed distinct diurnal expression patterns. In pineal gland, melanopsin mRNA levels were highest at night at Zeitgeber time (ZT) 16. In contrast, transcript levels in the whole retina reached their highest levels in the early morning (ZT 0-4). Further analysis of melanopsin mRNA expression in retinal layers isolated by laser capture microdissection revealed different patterns in different layers. There was diurnal expression in all retinal layers except the ganglion cell layer, where heavy expression was localized to a small number of cells. Expression of melanopsin mRNA peaked during the daytime in the retinal pigment epithelium and inner nuclear layer but, like in the pineal, at night in the photoreceptors. Localization and regulation of melanopsin mRNA in the retina and pineal gland is consistent with the hypothesis that this novel photopigment plays a role in photic regulation of circadian function in these tissues.

Amino Acid Sequence↗
PubMed2004

Asymptomatic carriers and gender differences in facioscapulohumeral muscular dystrophy (FSHD).

Facioscapulohumeral muscular dystrophy is an autosomal dominant muscle disorder, mapped to 4q35. It is characterized by remarkable inter- and intrafamilial clinical variability ranging from severe phenotype to asymptomatic carriers. The aim of the present study was to assess the size of the Eco RI fragment in a large sample of asymptomatic or minimally affected carriers as well as symptomatic patients, comparing both sexes, in order to verify if asymptomatic carriers are randomly distributed or concentrated in some particular families and if there is preferential parental transmission (maternal or paternal) resulting in non-penetrant carriers. We have analysed a total of 506 individuals from 106 unrelated families with at least one affected facioscapulohumeral muscular dystrophy proband. In all patients the molecular diagnosis was confirmed following double digestion (Eco RI/Bln I fragment <35 kb). About 20% among probands' relatives who were found to carry the small fragment were asymptomatic or minimally affected, without preferential parental transmission, but with a significantly higher proportion of females (n=37) than males (n=14). Although asymptomatic carriers were found in about 30% of the families, some genealogies seem to concentrate more non-penetrant cases. A significant correlation between the size of the Eco RI fragment and severity of the phenotype was observed in the total sample but surprisingly this correlation is significant only among affected females. The gender difference in clinical manifestation as well as the observation that asymptomatic carriers are not rare should be taken into consideration in genetic counseling of affected patients or 'at-risk' relatives.

Adult↗
PubMed2004

A novel stop codon mutation in the PMP22 gene associated with a variable phenotype.

The most frequent inherited peripheral neuropathy is the peripheral myelin protein 22 (PMP22) gene related disease. Duplication, deletion, and point mutations in that gene are associated with phenotypic variability. Here we report a family carrying a novel mutation in the PMP22 gene (c. 327C>A), which results in a premature stop codon (Cys109stop). The family members who carry this mutation have a Charcot-Marie-Tooth type 1 variable phenotype, ranging from asymptomatic to severely affected. These findings suggest that the fourth transmembrane domain of the PMP22 gene may play an important role, although the intrafamilial clinical variability reinforces the observation that pathogenic mutations are not always phenotype determinant and that other factors (genetic or epigenetic) modulate the severity of the clinical course.

Adolescent↗
PubMed2003

Protein defects in neuromuscular diseases.

Muscular dystrophies are a heterogeneous group of genetically determined progressive disorders of the muscle with a primary or predominant involvement of the pelvic or shoulder girdle musculature. The clinical course is highly variable, ranging from severe congenital forms with rapid progression to milder forms with later onset and a slower course. In recent years, several proteins from the sarcolemmal muscle membrane (dystrophin, sarcoglycans, dysferlin, caveolin-3), from the extracellular matrix (alpha2-laminin, collagen VI), from the sarcomere (telethonin, myotilin, titin, nebulin), from the muscle cytosol (calpain 3, TRIM32), from the nucleus (emerin, lamin A/C, survival motor neuron protein), and from the glycosylation pathway (fukutin, fukutin-related protein) have been identified. Mutations in their respective genes are responsible for different forms of neuromuscular diseases. Protein analysis using Western blotting or immunohistochemistry with specific antibodies is of the utmost importance for the differential diagnosis and elucidation of the physiopathology of each genetic disorder involved. Recent molecular studies have shown clinical inter- and intra-familial variability in several genetic disorders highlighting the importance of other factors in determining phenotypic expression and the role of possible modifying genes and protein interactions. Developmental studies can help elucidate the mechanism of normal muscle formation and thus muscle regeneration. In the last fifteen years, our research has focused on muscle protein expression, localization and possible interactions in patients affected by different forms of muscular dystrophies. The main objective of this review is to summarize the most recent findings in the field and our own contribution.

Blotting, Western↗
PubMed2003

The effect of calpain 3 deficiency on the pattern of muscle degeneration in the earliest stages of LGMD2A.

Limb girdle muscular dystrophy type 2A (LGMD2A) is caused by mutations in the calpain 3 gene. In a large family affected by LGMD2A with four severely affected members, three additional asymptomatic relatives had very high serum creatine kinase concentrations. All were homozygous for the R110X mutation and showed a total absence of calpain 3 in the muscle. Histological analysis of muscle in these three rare preclinical cases showed a consistent but unusual pattern, with isolated fascicles of degenerating fibres in an almost normal muscle. This pattern was also seen in one patient with early stage LGMD2A who had a P82L missense mutation and a partial deficiency of calpain 3 in the muscle, but was not seen in early stage patients affected by other forms of LGMD. These findings suggest that a peculiar pattern of focal degeneration occurs in calpainopathy, independently of the type of mutation or the amount of calpain 3 in the muscle.

Calpain↗
PubMed2002

Further evidence for a fourth gene causing X-linked pure spastic paraplegia.

X-linked hereditary spastic paraplegias (HSPs) present with two distinct phenotypes: pure and complicated. The pure form is characterized by slowly progressive weakness and spasticity of the lower limbs, whereas the complicated forms have additional features (optic neuropathy, retinopathy, extrapyramidal disturbance, dementia, epilepsy, ataxia, ichthyosis, mental retardation, and deafness). Three X-linked loci have been identified for the complicated HSP, while mutations in the proteolipid gene (PLP) (locus SPG2) were implicated in both pure and complicated forms. The absence of identified mutations in the PLP gene in families with both complicated and pure HSP, linked to the SPG2 locus, suggests the existence of another gene in close proximity. We had previously reported a large pedigree with an X-linked form of pure HSP affecting 24 males [Zatz et al., 1976: J Med Genet 13:217-222]. Here, we present the results of linkage analysis in 19 members of this Brazilian family with markers in or near the PLP locus. Positive LOD scores were obtained with markers at the PLP locus (Zmax = 2.41 at Theta = 0); however, no mutation was found in the coding region of PLP, the intron-exon boundaries, or part of the promoter region. The possibility of a duplication of the PLP gene was also excluded. These results suggest either that there is another X-linked gene in close proximity to the PLP gene or that a novel mutation in the noncoding regions of the PLP gene may cause the disease in this family.

Adolescent↗
PubMed2002

Lack of the C-terminal domain of nebulin in a patient with nemaline myopathy.

The most common autosomal recessive form of nemaline myopathy is due to mutations in the nebulin gene. Among eight patients studied, we identified one, a 14-year-old girl, with a specific pattern of diffuse rods in muscle fibers. Western blot analysis detected absence of the C-terminal domain of nebulin. Protein analysis may represent a good screening method to direct molecular studies in the case of very large and complex genes such as the large 1298 kb nebulin gene.

Adolescent↗
PubMed2002

Facioscapulohumeral (FSHD1) and other forms of muscular dystrophy in the same family: is there more in muscular dystrophy than meets the eye?

We report on two unrelated Brazilian families with members affected by two different forms of muscular dystrophy. In the first one, the 35-year-old male proband has limb-girdle muscular dystrophy with proximal weakness, elevated creatine kinase and a myopathic muscle biopsy. All the proteins known to be associated with limb-girdle muscular dystrophy were normal. Two of his sisters also complained of muscle weakness. The oldest sister showed clinical signs consistent with facioscapulohumeral muscular dystrophy, confirmed through molecular analysis. She presented a 30 kb EcoRI/BlnI fragment which was found in another six relatives, but surprisingly not in the affected proband or the other sister. In the second family, a 57-year-old male with a typical facioscapulohumeral muscular dystrophy phenotype has a 17 kb EcoRI/BlnI fragment, which was also present in other affected relatives. However in a 14-year-old severely affected male cousin, confined to a wheelchair since age 12, but without facial weakness, the small fragment was absent. These families illustrate the importance of testing all affected individuals in a family.

Adolescent↗
PubMed2001

Characterization of human skeletal muscle Ankrd2.

Human Ankrd2 transcript encodes a 37-kDa protein that is similar to mouse Ankrd2 recently shown to be involved in hypertrophy of skeletal muscle. These novel ankyrin-rich proteins are related to C-193/CARP/MARP, a cardiac protein involved in the control of cardiac hypertrophy. A human genomic region of 14,300 bp was sequenced revealing a gene organization similar to mouse Ankrd2 with nine exons, four of which encode ankyrin repeats. The intracellular localization of Ankrd2 was unknown since no protein studies had been reported. In this paper we studied the intracellular localization of the protein and its expression on differentiation using polyclonal and monoclonal antibodies produced to human Ankrd2. In adult skeletal muscle Ankrd2 is found in slow fibers; however, not all of the slow fibers express Ankrd2 at the same level. This is particularly evident in dystrophic muscles, where the expression of Ankrd2 in slow fibers seems to be severely reduced.

Animals↗
PubMed2001

Mutations in the caveolin-3 gene: When are they pathogenic?

Limb-girdle muscular dystrophies (LGMD) are a heterogeneous group of genetic disorders usually with autosomal recessive (AR) inheritance and, less often, displaying autosomal dominant (AD) inheritance. Mutations in the caveolin-3 gene (CAV-3) associated with a reduction of protein expression cause AD-LGMD1C muscular dystrophy. Based on a previous study in the American and Brazilian population, it has been suggested that CAV-3 mutations might also cause AR-LGMD. Here we report the analysis of the CAV-3 gene in 61 additional Brazilian LGMD patients and 100 additional Brazilian normal controls. Two rare G55S and C71W missense changes previously detected only in LGMD patients (and not detected in 100 normal controls from the American population) were now found in normal Brazilian controls. In addition, we have identified a novel R125H missense change in one LGMD female patient that was also found in two of her unaffected siblings. These observations, together with the normal immunofluorescence caveolin pattern in the muscle biopsy from two patients with the G55W and R125H changes in the CAV-3 gene suggest that the G55S, C71W, and R125H polymorphisms, on their own, are not sufficient to produce the pathology.

Adult↗
PubMed2001

No evidence of association between the D10S1423 locus and Alzheimer disease in Brazilian patients.

In a genome survey for Alzheimer's disease (AD), Zubenko et al. (1998) reported that the 234bp allele of the D10S1423 locus was more frequent among AD cases than in controls. We have analyzed this polymorphic locus in patients and healthy controls and observed that the 226bp allele is the most frequent allele in the D10S1423 locus in Brazilian AD patients. However, no statistically significant association between any D10S1423 allele was observed in AD patients as well as in controls.

Aged↗