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1.
Hear Res ; 196(1-2): 19-25, 2004 Oct.
Article in English | MEDLINE | ID: mdl-15464297

ABSTRACT

Insulin-like growth factors (IGFs) have a pivotal role during nervous system development and in its functional maintenance. IGF-I and its high affinity receptor (IGF1R) are expressed in the developing inner ear and in the postnatal cochlear and vestibular ganglia. We recently showed that trophic support by IGF-I is essential for the early neurogenesis of the chick cochleovestibular ganglion (CVG). In the chicken embryo otic vesicle, IGF-I regulates developmental death dynamics by regulating the activity and/or levels of key intracellular molecules, including lipid and protein kinases such as ceramide kinase, Akt and Jun N-terminal kinase (JNK). Mice lacking IGF-I lose many auditory neurons and present increased auditory thresholds at early postnatal ages. Neuronal loss associated to IGF-I deficiency is caused by apoptosis of the auditory neurons, which presented abnormally increased levels of activated caspase-3. It is worth noting that in man, homozygous deletion of the IGF-1 gene causes sensory-neural deafness. IGF-I is thus necessary for normal development and maintenance of the inner ear. The trophic actions of IGF-I in the inner ear suggest that this factor may have therapeutic potential for the treatment of hearing loss.


Subject(s)
Ear, Inner/embryology , Insulin-Like Growth Factor I/physiology , Animals , Animals, Newborn/growth & development , Cellular Senescence/physiology , Cochlea/cytology , Cochlea/growth & development , Embryonic Development/physiology
2.
J Immunol ; 169(8): 4637-43, 2002 Oct 15.
Article in English | MEDLINE | ID: mdl-12370403

ABSTRACT

Familial predisposition to IgA deficiency (IgAD) suggests that genetic factors influence susceptibility. Most studies support a polygenic inheritance with a susceptibility locus (designated IGAD1) in the MHC, but its exact location is still controversial. This study aimed to map the predisposing IGAD1 locus (or loci) within the MHC by investigating the pattern of association of the disease with several markers in the region. DNA-based techniques were used to type individual alleles of four polymorphic HLA genes (HLA-DR, -DQA1, -DQB1, and HLA-B), six microsatellites (all located between HLA-DR and HLA-B), and three single nucleotide polymorphisms on the TNF gene. The frequencies of these alleles were compared among ethnically matched populations comprising 182 patients and 343 controls. Additionally, we investigated parents and siblings of 100 of these patients. All four parental haplotypes were established in each family (n = 400), and transmission disequilibrium tests were performed. Surprisingly, our results did not support the hypothesis of a unique susceptibility gene being shared by all MHC susceptibility haplotypes. On HLA-DR1 and -DR7-positive haplotypes IGAD1 mapped to the class II region, whereas on haplotypes carrying HLA-DR3 the susceptibility locus mapped to the telomeric end of the class III region, as reported previously. Our results show how, in complex diseases, individuals may be affected for different genetic reasons and a single linkage signal to a region of a chromosome may actually be the result of disease-predisposing alleles in different linked genes in different pedigrees.


Subject(s)
Genes, MHC Class II , Genes, MHC Class I , Genetic Predisposition to Disease/genetics , HLA Antigens/genetics , Haplotypes/immunology , IgA Deficiency/genetics , IgA Deficiency/immunology , Alleles , Female , Gene Frequency/immunology , Genetic Markers/immunology , HLA Antigens/analysis , HLA-DR Antigens/analysis , HLA-DR Antigens/genetics , HLA-DR3 Antigen/analysis , HLA-DR3 Antigen/genetics , HLA-DR7 Antigen/analysis , HLA-DR7 Antigen/genetics , HLA-DRB1 Chains , Histocompatibility Testing/methods , Humans , Male , Polymerase Chain Reaction/methods
3.
Hum Immunol ; 63(5): 424-33, 2002 May.
Article in English | MEDLINE | ID: mdl-11975987

ABSTRACT

This study investigates the hypothesis that alternative alleles of one or more genes in the central major histocompatibility complex (MHC) predispose carriers to IgA deficiency (IgAD) or IgA Nephropathy (IgAN). Australian caucasian IgAD, IgAN patients, and controls were typed at HLA loci, single nucleotide polymorphisms, and microsatellites in the MHC. Alleles of the D6S273 microsatellite exhibited strong associations with IgAD and IgAN. D6S273*129 and *139 were more frequent in IgAD and less frequent in IgAN patients than controls. The reverse was true for D6S273*133 and *131. Alleles of other microsatellites exhibited weak associations with IgAD or IgAN. D6S273*129 is found on the 65.1 ancestral haplotype [HLA-B14(65),DR1], which has been reported to be increased in IgAD, but the majority of IgAD patients with D6S273*129 did not have other alleles of the haplotype. D6S273*139 is characteristic of the 8.1 ancestral haplotype (HLA-A1,B8,DR3), which was common in IgAD and rare in IgAN patients. Further studies of the 8.1 haplotype in Australian, German and Spanish caucasian subjects revealed that HLA-DR3, in the absence of -B8, is not associated with IgAD. However -B8 is associated with IgAD in the absence of -DR3, consistent with a susceptibility locus in the central MHC. Provisional mapping within this region is discussed.


Subject(s)
Genetic Predisposition to Disease , Glomerulonephritis, IGA/genetics , IgA Deficiency/genetics , Major Histocompatibility Complex/genetics , Australia , Cohort Studies , HLA-B8 Antigen/genetics , HLA-DR Antigens/genetics , HLA-DR Serological Subtypes , HLA-DR3 Antigen/genetics , Haplotypes , Humans , Immunoglobulin A/analysis , Telomere/genetics , White People
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