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1.
Transl Psychiatry ; 5: e568, 2015 May 19.
Article in English | MEDLINE | ID: mdl-25989142

ABSTRACT

Chromodomain helicase DNA-binding protein 8 (CHD8) was identified as a leading autism spectrum disorder (ASD) candidate gene by whole-exome sequencing and subsequent targeted-sequencing studies. De novo loss-of-function mutations were identified in 12 individuals with ASD and zero controls, accounting for a highly significant association. Small interfering RNA-mediated knockdown of CHD8 in human neural progenitor cells followed by RNA sequencing revealed that CHD8 insufficiency results in altered expression of 1715 genes, including both protein-coding and noncoding RNAs. Among the 10 most changed transcripts, 4 (40%) were noncoding RNAs. The transcriptional changes among protein-coding genes involved a highly interconnected network of genes that are enriched in neuronal development and in previously identified ASD candidate genes. These results suggest that CHD8 insufficiency may be a central hub in neuronal development and ASD risk.


Subject(s)
Autistic Disorder/genetics , DNA-Binding Proteins/genetics , Neural Stem Cells/metabolism , RNA, Messenger/genetics , RNA, Untranslated/genetics , Transcription Factors/genetics , Autism Spectrum Disorder/genetics , Cells, Cultured , Gene Expression Regulation, Developmental , Gene Knockdown Techniques , Humans , RNA, Small Interfering
2.
Transl Psychiatry ; 3: e316, 2013 Oct 22.
Article in English | MEDLINE | ID: mdl-24150225

ABSTRACT

Single nucleotide variants (SNV) in the gene encoding the MET receptor tyrosine kinase have been associated with an increased risk for autism spectrum disorders (ASD). The MET promoter SNV rs1858830 C 'low activity' allele is enriched in ASD, associated with reduced protein expression, and impacts functional and structural circuit connectivity in humans. To gain insight into the transcriptional regulation of MET on ASD-risk etiology, we examined an interaction between the methyl CpG-binding protein 2 (MeCP2) and the MET 5' promoter region. Mutations in MeCP2 cause Rett syndrome (RTT), a predominantly female neurodevelopmental disorder sharing some ASD clinical symptoms. MeCP2 binds to a region of the MET promoter containing the ASD-risk SNV, and displays rs1858830 genotype-specific binding in human neural progenitor cells derived from the olfactory neuroepithelium. MeCP2 binding enhances MET expression in the presence of the rs1858830 C allele, but MET transcription is attenuated by RTT-specific mutations in MeCP2. In the postmortem temporal cortex, a region normally enriched in MET, gene expression is reduced dramatically in females with RTT, although not due to enrichment of the rs1858830 C 'low activity' allele. We newly identified a sex-based reduction in MET expression, with male ASD cases, but not female ASD cases compared with sex-matched controls. The experimental data reveal a prominent allele-specific regulation of MET transcription by MeCP2. The mechanisms underlying the pronounced reduction of MET in ASD and RTT temporal cortex are distinct and likely related to factors unique to each disorder, including a noted sex bias.


Subject(s)
Autistic Disorder/genetics , Gene Expression Regulation/genetics , Methyl-CpG-Binding Protein 2/genetics , Proto-Oncogene Proteins c-met/genetics , Rett Syndrome/genetics , Temporal Lobe/metabolism , Autistic Disorder/metabolism , Female , Genotype , Humans , Male , Methyl-CpG-Binding Protein 2/metabolism , Mutation , Neuroepithelial Cells/metabolism , Phenotype , Polymorphism, Single Nucleotide , Promoter Regions, Genetic , Real-Time Polymerase Chain Reaction , Rett Syndrome/metabolism , Sex Factors
3.
Mol Psychiatry ; 16(1): 108-20, 2011 Jan.
Article in English | MEDLINE | ID: mdl-19806148

ABSTRACT

Genetic association studies of SLC6A4 (SERT) and obsessive-compulsive disorder (OCD) have been equivocal. We genotyped 1241 individuals in 278 pedigrees from the OCD Collaborative Genetics Study for 13 single-nucleotide polymorphisms, for the linked polymorphic region (LPR) indel with molecular haplotypes at rs25531, for VNTR polymorphisms in introns 2 and 7 and for a 381-bp deletion 3' to the LPR. We analyzed using the Family-Based Association Test (FBAT) under additive, dominant, recessive and genotypic models, using both OCD and sex-stratified OCD as phenotypes. Two-point FBAT analysis detected association between Int2 (P = 0.0089) and Int7 (P = 0.0187) (genotypic model). Sex-stratified two-point analysis showed strong association in females with Int2 (P<0.0002), significant after correction for linkage disequilibrium, and multiple marker and model testing (P(Adj) = 0.0069). The SLC6A4 gene is composed of two haplotype blocks (our data and the HapMap); FBAT whole-marker analysis conducted using this structure was not significant. Several noteworthy nonsignificant results have emerged. Unlike Hu et al., we found no evidence for overtransmission of the LPR L(A) allele (genotype relative risk = 1.11, 95% confidence interval: 0.77-1.60); however, rare individual haplotypes containing L(A) with P<0.05 were observed. Similarly, three individuals (two with OCD/OCPD) carried the rare I425V SLC6A4 variant, but none of them passed it on to their six OCD-affected offspring, suggesting that it is unlikely to be solely responsible for the 'OCD plus syndrome', as reported by Ozaki et al. In conclusion, we found evidence of genetic association at the SLC6A4 locus with OCD. A noteworthy lack of association at the LPR, LPR-rs25531 and rare 425V variants suggests that hypotheses about OCD risk need revision to accommodate these new findings, including a possible gender effect.


Subject(s)
Obsessive-Compulsive Disorder/genetics , Serotonin Plasma Membrane Transport Proteins/genetics , Adolescent , Adult , Child , Female , Genetic Predisposition to Disease , Haplotypes , Humans , Male , Pedigree , Polymorphism, Single Nucleotide , Sex Distribution , United States , Young Adult
4.
Mol Psychiatry ; 16(2): 193-201, 2011 Feb.
Article in English | MEDLINE | ID: mdl-20125088

ABSTRACT

A genome-wide association study was carried out in 1020 case subjects with recurrent early-onset major depressive disorder (MDD) (onset before age 31) and 1636 control subjects screened to exclude lifetime MDD. Subjects were genotyped with the Affymetrix 6.0 platform. After extensive quality control procedures, 671 424 autosomal single nucleotide polymorphisms (SNPs) and 25 068 X chromosome SNPs with minor allele frequency greater than 1% were available for analysis. An additional 1 892 186 HapMap II SNPs were analyzed based on imputed genotypic data. Single-SNP logistic regression trend tests were computed, with correction for ancestry-informative principal component scores. No genome-wide significant evidence for association was observed, assuming that nominal P<5 × 10(-8) approximates a 5% genome-wide significance threshold. The strongest evidence for association was observed on chromosome 18q22.1 (rs17077540, P=1.83 × 10(-7)) in a region that has produced some evidence for linkage to bipolar-I or -II disorder in several studies, within an mRNA detected in human brain tissue (BC053410) and approximately 75 kb upstream of DSEL. Comparing these results with those of a meta-analysis of three MDD GWAS data sets reported in a companion article, we note that among the strongest signals observed in the GenRED sample, the meta-analysis provided the greatest support (although not at a genome-wide significant level) for association of MDD to SNPs within SP4, a brain-specific transcription factor. Larger samples will be required to confirm the hypothesis of association between MDD (and particularly the recurrent early-onset subtype) and common SNPs.


Subject(s)
Depressive Disorder, Major/genetics , Genetic Predisposition to Disease , Genome-Wide Association Study , Polymorphism, Single Nucleotide/genetics , Adult , Aged , Chromosome Mapping , Europe , Female , Gene Frequency , Genotype , Humans , Logistic Models , Male , Microarray Analysis/methods , Middle Aged , Recurrence , Sex Factors , Sp4 Transcription Factor/genetics
5.
Bull Exp Biol Med ; 141(3): 347-52, 2006 Mar.
Article in English | MEDLINE | ID: mdl-17073157

ABSTRACT

Children, residents of the Russian Federation, with congenital isolated growth hormone deficiency, were screened for mutations of GH-1 gene, the main gene of this deficiency. Twenty-eight children from 26 families with total congenital isolated growth hormone deficiency were examined. Direct sequencing of GH-1 detected five splicing mutations in intron 2, intron 3, and exon 4, two of them were never described previously. Three dominant negative mutations of GH-1 splicing, the basis for autosomal dominant isolated growth hormone deficiency (type II), are presented: IVS2 -2A>T, IVS3 +2T>C, and IVS3 +1GA mutation can be regarded as the most incident in type II isolated growth hormone deficiency in the Russian population.


Subject(s)
Growth Hormone/deficiency , Mutation , RNA Splicing , Base Sequence , Child , Child, Preschool , DNA Primers , Female , Growth Hormone/genetics , Humans , Male , Pedigree
6.
Article in Russian | MEDLINE | ID: mdl-14564781

ABSTRACT

One hundred and three patients with spinal muscular atrophy (SMA) were registered in a population medical genetic study of autosomal recessive childhood proximal SMA in Saratov region. Twenty-five patients were investigated complexly, using biochemical analysis of some enzymes, electroneuromyography, magnetic resonance imaging of spinal cord, muscle biopsy and molecular genetic testing. Pronounced clinical polymorphism and genetic heterogeneity of the disease were revealed.


Subject(s)
Chromosomes, Human, Pair 5/genetics , Nerve Tissue Proteins/genetics , Spinal Muscular Atrophies of Childhood/genetics , Biopsy , Child , Cyclic AMP Response Element-Binding Protein , Female , Humans , Magnetic Resonance Imaging , Male , Muscle, Skeletal/pathology , Point Mutation/genetics , RNA-Binding Proteins , SMN Complex Proteins , Spinal Cord/pathology , Spinal Muscular Atrophies of Childhood/diagnosis
7.
Eur J Hum Genet ; 9(8): 646-50, 2001 Aug.
Article in English | MEDLINE | ID: mdl-11528513

ABSTRACT

Charcot-Marie-Tooth disease (CMT) constitutes a genetically heterogeneous group of inherited motor and sensory peripheral neuropathies. The axonal type of CMT is designated CMT type 2 (CMT2). Four loci for autosomal dominant CMT2 have been reported so far. Only in CMT2E, linked to chromosome 8p21, disease-causing mutations in the gene for neurofilament light chain (NEFL) were identified. In this study we report a multigenerational Russian family with autosomal dominant CMT2 and assign the locus to chromosome 7q11-q21. The CMT2 neuropathy in this family represents a novel genetic entity designated CMT2F.


Subject(s)
Charcot-Marie-Tooth Disease/genetics , Chromosome Mapping , Chromosomes, Human, Pair 7/genetics , Genes, Dominant/genetics , Adolescent , Adult , Child , Child, Preschool , Female , Genetic Markers/genetics , Humans , Infant , Infant, Newborn , Male , Pedigree
9.
Ann Neurol ; 49(2): 245-9, 2001 Feb.
Article in English | MEDLINE | ID: mdl-11220745

ABSTRACT

A missense mutation in the neurofilament light chain gene (NEFL, NF-L) at chromosome 8p21 was recently reported in a single Charcot-Marie-Tooth type 2 family (CMT2). This new CMT2 variant is designated CMT2E. The NEFL gene mutation showed co-segregation with the disease phenotype and is thus most likely the disease-causing mutation. However, the possibility that it is a closely linked rare polymorphism can not be ruled out with certainty. We observed a novel NEFL missense mutation in a second CMT family, providing supporting evidence that CMT2E is caused by NEFL gene mutations.


Subject(s)
Charcot-Marie-Tooth Disease/genetics , Neurofilament Proteins/genetics , Adolescent , Chromatography, High Pressure Liquid , Female , Humans , Mutation/genetics , Pedigree , Time Factors
11.
Am J Hum Genet ; 67(6): 1526-43, 2000 Dec.
Article in English | MEDLINE | ID: mdl-11078479

ABSTRACT

Clinal patterns of autosomal genetic diversity within Europe have been interpreted in previous studies in terms of a Neolithic demic diffusion model for the spread of agriculture; in contrast, studies using mtDNA have traced many founding lineages to the Paleolithic and have not shown strongly clinal variation. We have used 11 human Y-chromosomal biallelic polymorphisms, defining 10 haplogroups, to analyze a sample of 3,616 Y chromosomes belonging to 47 European and circum-European populations. Patterns of geographic differentiation are highly nonrandom, and, when they are assessed using spatial autocorrelation analysis, they show significant clines for five of six haplogroups analyzed. Clines for two haplogroups, representing 45% of the chromosomes, are continentwide and consistent with the demic diffusion hypothesis. Clines for three other haplogroups each have different foci and are more regionally restricted and are likely to reflect distinct population movements, including one from north of the Black Sea. Principal-components analysis suggests that populations are related primarily on the basis of geography, rather than on the basis of linguistic affinity. This is confirmed in Mantel tests, which show a strong and highly significant partial correlation between genetics and geography but a low, nonsignificant partial correlation between genetics and language. Genetic-barrier analysis also indicates the primacy of geography in the shaping of patterns of variation. These patterns retain a strong signal of expansion from the Near East but also suggest that the demographic history of Europe has been complex and influenced by other major population movements, as well as by linguistic and geographic heterogeneities and the effects of drift.


Subject(s)
Genetic Variation/genetics , Geography , Language , Y Chromosome/genetics , Africa, Northern , Alleles , Emigration and Immigration , Europe , Gene Frequency/genetics , Genetic Markers/genetics , Haplotypes/genetics , Humans , Linguistics , Male , Models, Genetic , Oceans and Seas , Phylogeny , Polymorphism, Genetic/genetics
12.
Genetika ; 36(8): 1150-6, 2000 Aug.
Article in Russian | MEDLINE | ID: mdl-11033788

ABSTRACT

Polymorphism of the DYS19 and DYS393 microsatellite loci and T-C transition at the RBF5 locus of the Y chromosome were analyzed in Volga-Ural populations of Bashkirs, Tatars, Chuvashes, Maris, Mordovians, Udmurts, and Komis. For the DYS19 locus, statistically significant differences were observed between Trans-Ural and Northeastern Bashkirs; between Trans-Ural Bashkirs and Tatars; and between Udmurts and other populations of the Volga-Ural region, excluding Trans-Ural Bashkirs. The DYS393 locus allele frequency distribution patterns were similar in all populations studied. The highest and the lowest frequencies of T-C transition at the RBF5 locus was detected in Udmurts (0.68) and in Mordovians (0.09), respectively. Association of C-alleles with the DYS19/DYS393 microsatellite haplotypes was investigated. The major haplotypes specific to the Turkic- and Finno-Ugric populations were revealed.


Subject(s)
Chromosome Mapping , Microsatellite Repeats/genetics , Polymorphism, Genetic , Y Chromosome , Base Sequence , DNA Primers , Humans , Russia
13.
Genetika ; 36(7): 972-9, 2000 Jul.
Article in Russian | MEDLINE | ID: mdl-10994503

ABSTRACT

Mutations of the Wilson disease (WD) gene were studied in patients from Bashkortostan. Four mutations were identified: His1069Gln, 3402delC, Glu1064Lys, and 3559 + 1G-->T. The latter mutation was described for the first time. Mutation His1069Gln was found to be the most prevalent in Bashkortostan; its frequency was 43.5%. The associations of the mutations found with the haplotypes for polymorphic loci D13S316, D13S133, and D13S228 were studied. The mutations were found to be linked with specific haplotypes, and the study of polymorphic haplotypes can therefore facilitate the search for mutations in the gene for WD. The results of the molecular genetic study of WD can be used for direct and indirect DNA diagnostics of this disease in Bashkortostan.


Subject(s)
Genetic Markers , Haplotypes , Hepatolenticular Degeneration/genetics , Mutation , Polymorphism, Genetic , Base Sequence , DNA Primers , Hepatolenticular Degeneration/epidemiology , Humans , Prevalence , Russia/epidemiology
14.
Am J Hum Genet ; 67(1): 37-46, 2000 Jul.
Article in English | MEDLINE | ID: mdl-10841809

ABSTRACT

Charcot-Marie-Tooth (CMT) disease is the most common inherited motor and sensory neuropathy. The axonal form of the disease is designated as "CMT type 2" (CMT2). Although four loci known to be implicated in autosomal dominant CMT2 have been mapped thus far (on 1p35-p36, 3q13. 1, 3q13-q22, and 7p14), no one causative gene is yet known. A large Russian family with CMT2 was found in the Mordovian Republic (Russia). Affected members had the typical CMT2 phenotype. Additionally, several patients suffered from hyperkeratosis, although the association, if any, between the two disorders is not clear. Linkage with the CMT loci already known (CMT1A, CMT1B, CMT2A, CMT2B, CMT2D, and a number of other CMT-related loci) was excluded. Genomewide screening pinpointed the disease locus in this family to chromosome 8p21, within a 16-cM interval between markers D8S136 and D8S1769. A maximum two-point LOD score of 5.93 was yielded by a microsatellite from the 5' region of the neurofilament-light gene (NF-L). Neurofilament proteins play an important role in axonal structure and are implicated in several neuronal disorders. Screening of affected family members for mutations in the NF-L gene and in the tightly linked neurofilament-medium gene (NF-M) revealed the only DNA alteration linked with the disease: a A998C transversion in the first exon of NF-L, which converts a conserved Gln333 amino acid to proline. This alteration was not found in 180 normal chromosomes. Twenty unrelated CMT2 patients, as well as 26 others with an undetermined form of CMT, also were screened for mutations in NF-L, but no additional mutations were found. It is suggested that Gln333Pro represents a rare disease-causing mutation, which results in the CMT2 phenotype.


Subject(s)
Charcot-Marie-Tooth Disease/genetics , Genetic Linkage/genetics , Genetic Variation/genetics , Mutation, Missense/genetics , Neurofilament Proteins/genetics , Amino Acid Sequence , Base Sequence , Child , Chromosome Mapping , Chromosomes, Human, Pair 8/genetics , DNA Mutational Analysis , Female , Humans , Lod Score , Male , Microsatellite Repeats/genetics , Molecular Sequence Data , Pedigree , Polymorphism, Single-Stranded Conformational
15.
Hum Mutat ; 15(4): 340-7, 2000.
Article in English | MEDLINE | ID: mdl-10737979

ABSTRACT

Charcot-Marie-Tooth disease (CMT) and related inherited peripheral neuropathies, including Dejerine-Sottas syndrome, congenital hypomyelination, and hereditary neuropathy with liability to pressure palsies (HNPP), are caused by mutations in three myelin genes: PMP22, MPZ and Cx32 (GJB1). The most common mutations are the 1.5 Mb CMT1A tandem duplication on chromosome 17p11.2-p12 in CMT1 patients and the reciprocal 1.5 Mb deletion in HNPP patients. We performed a mutation screening in 174 unrelated CMT patients and three HNPP families of Russian origin. The unrelated CMT patients included 108 clinically and electrophysiologically diagnosed CMT1 cases, 32 CMT2 cases, and 34 cases with unspecified CMT. Fifty-nine CMT1A duplications were found, of which 58 belonged to the CMT1 patient group. We found twelve distinct mutations in Cx32, six mutations in MPZ, and two mutations in PMP22. Of these respectively, eight, five, and two lead to a CMT1 phenotype. Eight mutations (Cx32: Ile20Asn/Gly21Ser, Met34Lys, Leu90Val, and Phe193Leu; MPZ: Asp134Gly, Lys138Asn, and Thr139Asn; PMP22: ValSer25-26del) were not reported previously. Phenotype-genotype correlations were based on nerve conduction velocity studies and mutation type.


Subject(s)
Charcot-Marie-Tooth Disease/genetics , Connexins/genetics , Myelin P0 Protein/genetics , Myelin Proteins/genetics , Adult , DNA Mutational Analysis , Female , Gene Duplication , Genetic Testing , Humans , Male , Gap Junction beta-1 Protein
16.
Hum Hered ; 49(3): 129-32, 1999 Jun.
Article in English | MEDLINE | ID: mdl-10364675

ABSTRACT

Familial benign polycythemia (FBP) (OMIM 263400) is a rare autosomal recessive condition characterized by erythrocytosis, normal leukocyte and platelet counts, normal uric acid level, and usually increased erythropoietin production. There is a high incidence of this disorder in Chuvashia (Russian Federation), probably due to a founder effect. In an attempt to locate the gene responsible for this disorder, we have carried out linkage studies in 12 Chuvash families, with 35 affected and 32 unaffected members. Linkage to the erythropoietin and erythropoietin receptor loci was excluded, and the FBP gene was assigned to the region of chromosome 11q23 between D11S4142 and D11S1356, with a maximal lod score of 6.61.


Subject(s)
Chromosomes, Human, Pair 11/genetics , Polycythemia/genetics , Chromosome Mapping , DNA/genetics , Family Health , Female , Genotype , Haplotypes , Humans , Male , Microsatellite Repeats , Phenotype , Polycythemia/pathology
17.
Genetika ; 34(7): 876-82, 1998 Jul.
Article in Russian | MEDLINE | ID: mdl-9749328

ABSTRACT

The number of dysrophin-positive fibers appearing in the femoral quadriceps muscle of mdx mice after injection of the full-length human dystrophin cDNA within the pHSADy plasmid was examined by means of immunohystochemical techniques. Transfection was carried out using lipofectamine (LFA), or synthetic oligopeptide complexes that provided the condensation of plasmid DNA (K8) and its release from endosomes gopeptide complexes that provided the condensation of plasmid DNA (K8) and its release from endosomes (JTS1). The LFA + pHSADy at a dose of 10 micrograms DNA did not affect the number of dystrophin-positive fibers at the site of injection (0.6-0.8%), whereas it caused a statistically significant increase in the number of these fibers in the same muscle of the contralateral leg (up to 2.3%). Injection of the SO + pHSADy complex resulted in the occurrence of dystrophin-positive muscle fibers characterized by a heterogeneous content and the distribution of dystrophin. The greatest number of dystrophin-positive fibers (about 16%) was observed under a ratio of pHSADy to K8 of 1:3 or 1:4. The observed maximal number of dystrophin-positive fibers after a single injection of SO + pHSADy was 3.8%, and it was 17.7% after three injections. These values were statistically significantly higher compared to intact mice (0.6%), the injection of pure plasmid (2.2%), or the intramuscular injection of sucrose (from 0.7 to 1.3%). A relatively high level of transfection (about 5%) was observed after an intracardiac injection of a large dose of the pHSADy (70 micrograms DNA). The perspectives of the targeted delivery of the dystrophin gene into muscles under conditions of parenteral administration are discussed.


Subject(s)
Dystrophin/genetics , Gene Expression Regulation/physiology , Muscle Fibers, Skeletal/metabolism , Transfection , Amino Acid Sequence , Animals , Cation Exchange Resins/administration & dosage , Drug Carriers , Genetic Therapy , Genetic Vectors , Humans , Lipids/administration & dosage , Liposomes , Male , Mice , Mice, Inbred mdx , Molecular Sequence Data , Muscular Dystrophy, Animal/therapy , Oligopeptides/administration & dosage
18.
Genetika ; 34(6): 730-6, 1998 Jun.
Article in Russian | MEDLINE | ID: mdl-9719921

ABSTRACT

"Gene-gun" ballistic transfection (BT) was used to deliver genetic constructs pMLVDy and pHSADy containing full-length cDNA of the dystrophin gene to musculus quadriceps remoris and musculus gluteus of mdx mice, which represent a natural model of Duchenne muscular dystrophy. Clusters of dystrophin-positive muscular fibers (DPMF) were immunocytochemically detected in sites exposed to BT. The average number of DPMF was 2% by the 17th day and 3% by the 60th day after BT with pMLVDy, whereas the number of revertant DPMF was 0.2% in control mice (without BT). When pHSADy was used, the average number of DPMF was 3% 20 days after BT. In this case, dystrophin was uniformly spread though the myoplasm in 3% of cells and produced a slight signal in separate regions under the sarcolemma in 10% of muscle fibers. The number of revertant DPMF increased to 0.6% after BT with naked particles and to 2.8% after BT with the marker lacZ gene, in both bombarded and contralateral legs. The number of DPMF in the corresponding muscles of the contralateral leg significantly increased and reached 2.8% by the 60th day after BT with pMLVDy and 6.7% by the 20th day after BT with pHSADy. Human dystrophin gene cDNA was detected in all skeletal muscles, heart, intestine, tongue, and brain by polymerase chain reaction (PCR) three weeks after BT. Immunoblot analysis showed that normal 427-kDa human dystrophin was synthesized in muscles of mdx mice. The results suggest applicability of BT for delivery of dystrophin constructs into muscles.


Subject(s)
Biolistics , Dystrophin/genetics , Muscle, Skeletal/metabolism , Muscular Dystrophy, Animal/genetics , Animals , DNA, Complementary , Dystrophin/metabolism , Humans , Immunohistochemistry , Male , Mice , Mice, Inbred C57BL , Mice, Inbred mdx
20.
J Clin Endocrinol Metab ; 83(7): 2601-4, 1998 Jul.
Article in English | MEDLINE | ID: mdl-9661653

ABSTRACT

Mutations in the prophet of Pit-1 gene (PROP1) have been shown to be responsible for combined pituitary hormone deficiency (CPHD) with deficiencies of growth hormone (GH), Prolactin (Prl), thyroid-stimulating hormone (TSH) and gonadotropins. We previously reported that homozygosity for a 2bp deletion in exon 2 (296delGA) accounted for CPHD in three patients from two Russian families. Here we report a second mutational hot spot in exon 2. This 2bp 149delGA deletion results in a frame shift that leads to the same serine to stop codon change at codon 109 (S109X). The predicted proteins are each truncated at residue 108 but diverge from the wild type sequence at different points in the homeodomain. Compound heterozygosity for the two mutations (149delGA/296delGA) was detected in 5 of 14 CPHD children from 4 families (36%). This provides the first evidence of heterozygosity for two common deletions as a cause of CPHD in Russian children.


Subject(s)
Gene Deletion , Heterozygote , Homeodomain Proteins/genetics , Pituitary Hormones/deficiency , Transcription Factors/genetics , Adolescent , Child , Child, Preschool , Female , Humans , Male , Russia
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