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1.
Clin Lab ; 64(11)2018 Oct 31.
Article in English | MEDLINE | ID: mdl-30549999

ABSTRACT

BACKGROUND: X-linked thrombocytopenia (XLT) is a milder form of Wiskott-Aldrich syndrome (WAS), characterized predominantly by thrombocytopenia with small-sized platelets. Mutations in the WAS gene are responsible for the disease. We herein detected a new mutation in the WAS gene responsible for XLT in a 3-generation Chinese pedigree. METHODS: Peripheral blood samples were collected from 7 members in the family. WAS gene was amplified from genomic DNA isolated from leucocytes, and then direct sequencing was performed. RESULTS: Three male members of this family (the proband, his younger brother and maternal uncle) had thrombocytopenia and decreased mean platelet volume. A homozygous mutation (T>C) was found at nucleotide position 319 in exon 3, causing the amino acid Tyr (T) to be abnormally changed to His (H) at position 107. Two female members (the proband's mother and grandmother) were carriers of the mutation. CONCLUSIONS: XLT is easy to misdiagnose as immune thrombocytopenic purpura (ITP). The diagnosis of XLT should be considered in any male with congenital microthrombocytopenia or early onset of microthrombocytope-nia (< 7 fL). This article adds to the growing number of known mutations associated with XLT.


Subject(s)
Genetic Diseases, X-Linked/genetics , Mutation, Missense , Thrombocytopenia/genetics , Wiskott-Aldrich Syndrome Protein/genetics , Wiskott-Aldrich Syndrome/genetics , Adolescent , Asian People/genetics , Base Sequence , China , DNA Mutational Analysis , Exons/genetics , Female , Genetic Diseases, X-Linked/blood , Genetic Diseases, X-Linked/ethnology , Humans , Male , Mean Platelet Volume , Pedigree , Thrombocytopenia/blood , Thrombocytopenia/ethnology , Wiskott-Aldrich Syndrome/blood , Wiskott-Aldrich Syndrome/ethnology
2.
J Genet ; 97(2): 411-417, 2018 Jun.
Article in English | MEDLINE | ID: mdl-29932061

ABSTRACT

TBX22 is a gene which contribute to cleft lip/palate, and many mutation sites of TBX22 have been reported. However, the exact role of TBX22 mutation in Chinese nonsyndromic cleft lip/palate (NSCL/P) family was not clearly explored. In this study, we tried to investigate the profiles and effects of TBX22 mutation in Chinese NSCL/P family. Members of two Chinese NSCL/P families and 200 normal controls were enrolled in this study. Further, DNA sequence and bioinformatic analysis for TBX22 were performed. The results showed that a novel and essential splicing site mutation, IVS6-1G>C , was detected in a family with cleft palate. The bioinformatic analysis results showed that this mutation would lead to abnormal transcription or translation, followed by a loss of function of TBX22. In addition, a hemizygous missense mutation, c.874G>A (p.D292N), was first reported in another Chinese family, which may exhibit aggravated effects on the phenotypes of CL/P. Taking these findings together, this study provides a profile of TBX22 mutation in Chinese NSCL/P families, and further confirmed the important role of TBX22 in familial cases with X-linked cleft palate.


Subject(s)
Cleft Lip/genetics , Cleft Palate/genetics , Genetic Diseases, X-Linked/genetics , Genetic Predisposition to Disease/genetics , Mutation , T-Box Domain Proteins/genetics , Amino Acid Sequence , Asian People/genetics , Base Sequence , China , Cleft Lip/ethnology , Cleft Palate/ethnology , DNA Mutational Analysis , Family Health , Female , Genetic Diseases, X-Linked/ethnology , Genetic Predisposition to Disease/ethnology , Humans , Male , Pedigree , Sequence Homology, Amino Acid
3.
Sci Rep ; 8(1): 2398, 2018 02 05.
Article in English | MEDLINE | ID: mdl-29402928

ABSTRACT

Nance-Horan syndrome is a rare X-linked recessive inherited disease with clinical features including severe bilateral congenital cataracts, characteristic facial and dental abnormalities. Data from Chinese Nance-Horan syndrome patients are limited. We assessed the clinical manifestations of a Chinese Nance-Horan syndrome pedigree and identified the genetic defect. Genetic analysis showed that 3 affected males carried a novel small deletion in NHS gene, c.263_266delCGTC (p.Ala89TrpfsTer106), and 2 female carriers were heterozygous for the same variant. All 3 affected males presented with typical Nance-Horan syndrome features. One female carrier displayed lens opacities centered on the posterior Y-suture in both eyes, as well as mild dental abnormalities. We recorded the clinical features of a Chinese Nance-Horan syndrome family and broadened the spectrum of mutations in the NHS gene.


Subject(s)
Cataract/congenital , Cataract/genetics , Genetic Diseases, X-Linked/genetics , Lens, Crystalline/metabolism , Nuclear Proteins/genetics , Sequence Deletion , Tooth Abnormalities/genetics , Adult , Asian People , Base Sequence , Cataract/ethnology , Cataract/pathology , Chromosomes, Human, X/chemistry , Dentition, Permanent , Female , Gene Expression , Genes, Recessive , Genetic Diseases, X-Linked/ethnology , Genetic Diseases, X-Linked/pathology , Heterozygote , Homozygote , Humans , Lens, Crystalline/pathology , Male , Membrane Proteins , Middle Aged , Nuclear Proteins/metabolism , Pedigree , Tooth Abnormalities/ethnology , Tooth Abnormalities/pathology
4.
PLoS One ; 12(9): e0185084, 2017.
Article in English | MEDLINE | ID: mdl-28934280

ABSTRACT

A recent study found that three recurrent deletions of X chromosome linked copy number variations (CNVs), CNV64, CNV67 and CNV69 were associated with idiopathic male infertility in Spanish and Italian populations, especially CNV67 resembling the azoospermia factor deletions. That merits further investigations among different populations. This study was conducted to examine the prevalence of the three CNVs deletions and their associations with idiopathic male infertility in Chinese Han population. The present study included a large population of 1550 Chinese Han subjects recruited between 2014 and 2016. In total, 714 infertile participants were diagnosed as idiopathic infertility with different conditions (288 with non-obstructive azoospermia, 210 oligozoospermia and 216 asthenospermia) and 836 fertile participants (vasectomized men). The fertile participants were recruited from the representative areas: the north (Hebei and Shanxi), center (Hubei and Jiangsu), and south (Guangdong) of China. All patients were recruited from Hubei province. A multiplex PCR system was established to screen the deletion of the three CNVs, and deletion was confirmed by general PCR. Similar rates of these deletions were observed in infertile men and fertile participants (Hubei), and among the different conditions of infertility. Moreover, CNV64 and CNV67 map distribution geographically differed across China. The three CNVs in fertile groups of other regions were similar, except for Guangdong. No association between the three CNVs deletions and idiopathic male infertility was observed. CNV67 is rare in central China, albeit large sample size study for confirmation is warranted. It seems that the association between these CNVs deletions and idiopathic male infertility is ethnic dependent. There is still need to screen the CNVs deletions in other ethnicities. We suggested to consider the stratification patterns and geographic differences when prescribing CNVs deletions screening as a test in male infertility.


Subject(s)
Chromosomes, Human, X , DNA Copy Number Variations , Infertility, Male/genetics , Sequence Deletion , Adult , Aged , Aged, 80 and over , Asian People/genetics , China , Chromosome Mapping , Genetic Diseases, X-Linked/ethnology , Genetic Diseases, X-Linked/genetics , Humans , Infertility, Male/ethnology , Male , Middle Aged , Vasectomy , Young Adult
5.
J Pediatr Hematol Oncol ; 39(5): 408-409, 2017 07.
Article in English | MEDLINE | ID: mdl-28644307

ABSTRACT

Dimorphism in peripheral blood film was noted in a 16 year old Malay boy with anemia who was eventually diagnosed with X-linked sideroblastic anemia. A mutation in ALAS2 S568G was identified which has not been described previously in a Malay ethnic group.


Subject(s)
5-Aminolevulinate Synthetase/genetics , Anemia, Sideroblastic/diagnosis , Genetic Diseases, X-Linked/diagnosis , Mutation , Adolescent , Anemia, Sideroblastic/drug therapy , Anemia, Sideroblastic/ethnology , Anemia, Sideroblastic/genetics , Genetic Diseases, X-Linked/drug therapy , Genetic Diseases, X-Linked/ethnology , Genetic Diseases, X-Linked/genetics , Hemoglobins/analysis , Humans , Malaysia , Male , Pyridoxine/therapeutic use , Sex Characteristics
6.
Curr Eye Res ; 42(9): 1240-1244, 2017 09.
Article in English | MEDLINE | ID: mdl-28557584

ABSTRACT

PURPOSE: To describe ocular and extraocular abnormalities in two Ashkenazi Jewish families with infantile cataract and X-linked inheritance, and to identify their underlying mutations. METHODS: Seven affected members were recruited. Medical history, clinical findings, and biometric measurements were recorded. Mutation analysis of the Nance-Horan syndrome (NHS) gene was performed by direct sequencing of polymerase chain reaction-amplified exons. RESULTS: An unusual anterior Y-sutural cataract was documented in the affected male proband. Other clinical features among examined patients included microcorneas, long and narrow faces, and current or previous dental anomalies. A nonsense mutation was identified in each family, including a previously described 742 C>T, p.(Arg248*) mutation in Family A, and a novel mutation 2915 C>A, p.(Ser972*) in Family B. CONCLUSIONS: Our study expands the repertoire of NHS mutations and the related phenotype, including newly described anterior Y-sutural cataract and dental findings.


Subject(s)
Cataract/congenital , DNA/genetics , Ethnicity , Genetic Diseases, X-Linked/genetics , Mutation , Nuclear Proteins/genetics , Tooth Abnormalities/genetics , Adult , Cataract/ethnology , Cataract/genetics , Cataract/metabolism , DNA Mutational Analysis , Exons , Female , Genetic Diseases, X-Linked/ethnology , Genetic Diseases, X-Linked/metabolism , Humans , Male , Membrane Proteins , Nuclear Proteins/metabolism , Pedigree , Phenotype , Polymerase Chain Reaction , Tooth Abnormalities/ethnology , Tooth Abnormalities/metabolism
8.
J Investig Allergol Clin Immunol ; 25(3): 205-13, 2015.
Article in English | MEDLINE | ID: mdl-26182687

ABSTRACT

BACKGROUND: X-linked lymphoproliferative syndrome type 2 is a rare hereditary immunodeficiency caused by mutations in the XIAP gene. This immunodeficiency frequently results in hemophagocytic lymphohistiocytosis, although hypogammaglobulinemia and dysgammaglobulinemia are also common. OBJECTIVE: We identified 17 patients from 12 Japanese families with mutations in XIAP. The Glu349del mutation was observed in 3 patients, each from a different family. Interestingly, these patients exhibited dysgammaglobulinemia but not hemophagocytic lymphohistiocytosis. We conducted an immunological study of patients carrying Glu349del and other mutations to elucidate the pathogenic mechanisms of dysgammaglobulinemia in patients with mutations in the XIAP gene. PATIENTS AND METHODS: We performed an immunological study of 2 patients carrying the Glu349del mutation and 8 patients with other mutations. RESULTS: Flow cytometry showed that the percentage of memory B cells in patients with a mutation in XIAP was lower than that observed in the healthy controls. The patients with the Glu349del mutation had a lower percentage of memory B cells than those with other mutations. Ig production was reduced in patients with the Glu349del mutation. Increased susceptibility to apoptosis was observed in the patients with other mutations. Susceptibility to apoptosis was normal in patients with Glu349del. Microarray analysis indicated that expression of Ig-related genes was reduced in patients with the Glu349del mutation and that the pattern was different from that observed in the healthy controls or patients with other mutations in XIAP. CONCLUSIONS: Patients carrying the Glu349del mutation in the XIAP gene may have a clinically and immunologically distinct phenotype from patients with other XIAP mutations. The Glu349del mutation may be associated with dysgammaglobulinemia.


Subject(s)
Dysgammaglobulinemia/genetics , Genetic Diseases, X-Linked/genetics , Lymphoproliferative Disorders/genetics , Mutation , X-Linked Inhibitor of Apoptosis Protein/genetics , Adolescent , Apoptosis , Asian People/genetics , B-Lymphocytes/immunology , Case-Control Studies , Cells, Cultured , Child , Child, Preschool , DNA Mutational Analysis , Dysgammaglobulinemia/diagnosis , Dysgammaglobulinemia/ethnology , Dysgammaglobulinemia/immunology , Female , Flow Cytometry , Gene Expression Profiling/methods , Genetic Diseases, X-Linked/diagnosis , Genetic Diseases, X-Linked/ethnology , Genetic Diseases, X-Linked/immunology , Genetic Predisposition to Disease , Humans , Immunologic Memory , Immunophenotyping/methods , Infant , Japan , Lymphoproliferative Disorders/diagnosis , Lymphoproliferative Disorders/ethnology , Lymphoproliferative Disorders/immunology , Male , Oligonucleotide Array Sequence Analysis , Pedigree , Phenotype , T-Lymphocytes/immunology , T-Lymphocytes/pathology
9.
BMC Med Genet ; 16: 9, 2015 Feb 25.
Article in English | MEDLINE | ID: mdl-25928534

ABSTRACT

BACKGROUND: Mutations in the POU3F4 gene cause X-linked deafness type 3 (DFN3), which is characterized by inner ear anomalies. METHODS: Three Turkish, one Ecuadorian, and one Nigerian families were included based on either inner ear anomalies detected in probands or X-linked family histories. Exome sequencing and/or Sanger sequencing were performed in order to identify the causative DNA variants in these families. RESULTS: Four novel, c.707A>C (p.(Glu236Ala)), c.772delG (p.(Glu258ArgfsX30)), c.902C>T (p.(Pro301Leu)), c.987T>C (p.(Ile308Thr)), and one previously reported mutation c.346delG (p.(Ala116ProfsX26)) in POU3F4, were identified. All mutations identified are predicted to affect the POU-specific or POU homeo domains of the protein and co-segregated with deafness in all families. CONCLUSIONS: Expanding the spectrum of POU3F4 mutations in different populations along with their associated phenotypes provides better understanding of their clinical importance and will be helpful in clinical evaluation and counseling of the affected individuals.


Subject(s)
Deafness/genetics , Genetic Diseases, X-Linked/genetics , POU Domain Factors/chemistry , POU Domain Factors/genetics , Child, Preschool , Cohort Studies , Deafness/ethnology , Female , Genetic Diseases, X-Linked/ethnology , Humans , Male , Models, Molecular , Pedigree , Protein Structure, Tertiary
10.
BMC Nephrol ; 15: 175, 2014 Nov 07.
Article in English | MEDLINE | ID: mdl-25381091

ABSTRACT

BACKGROUND: Collagen IV-related nephropathies, including thin basement membrane nephropathy and Alport Syndrome (AS), are caused by defects in the genes COL4A3, COL4A4 and COL4A5. Diagnosis of these conditions can be hindered by variable penetrance and the presence of non-specific clinical or pathological features. METHODS: Three families with unexplained inherited kidney disease were recruited from Shanghai, China. Whole exome sequencing (WES) was performed in the index case from each family and co-segregation of candidate pathogenic mutations was tested by Sanger sequencing. RESULTS: We identified COL4A4 missense variants [c.G2636A (p.Gly879Glu) and c.C4715T (p.Pro1572Leu)] in the 21-year-old male proband from family 1, who had been diagnosed with mesangial proliferative nephropathy at age 14. COL4A4 c.G2636A, a novel variant, co-segregated with renal disease among maternal relatives. COL4A4 c.C4715T has previously been associated with autosomal recessive AS and was inherited from his clinically unaffected father. In family 2, a novel COL4A3 missense mutation c.G2290A (p.Gly997Glu) was identified in a 45-year-old male diagnosed with focal segmental glomerulosclerosis and was present in all his affected family members, who exhibited disease ranging from isolated microscopic hematuria to end stage renal disease (ESRD). In family 3, ESRD occurred in both male and females who were found to harbor a known AS-causing COL4A5 donor splice site mutation (c.687+1G>A). None of these variants were detected among 100 healthy Chinese individuals. CONCLUSION: WES identified 2 novel and 2 known pathogenic COL4A3/COL4A4/COL4A5 mutations in 3 families with previously unexplained inherited kidney disease. These findings highlight the clinical range of collagen IV-related nephropathies and resolved diagnostic confusion arising from atypical or incomplete clinical/histological findings, allowing appropriate counselling and treatment advice to be given.


Subject(s)
Asian People/genetics , Autoantigens/genetics , Collagen Type IV/genetics , Collagen Type VI/genetics , Exome/genetics , Kidney Diseases/genetics , Mutation, Missense , Point Mutation , Pseudogenes/genetics , Sequence Analysis, DNA/methods , Aged , Amino Acid Substitution , China/epidemiology , Chromosomes, Human, Pair 2/genetics , Chromosomes, Human, X/genetics , DNA Mutational Analysis , Female , Genes, X-Linked , Genetic Diseases, X-Linked/ethnology , Genetic Diseases, X-Linked/genetics , Glomerulonephritis, Membranoproliferative/genetics , Glomerulosclerosis, Focal Segmental/genetics , Humans , Kidney Diseases/ethnology , Male , Middle Aged , Nephrotic Syndrome/genetics , Pedigree , Sequence Alignment , Sequence Homology, Amino Acid , Young Adult
11.
Clin Chim Acta ; 425: 30-3, 2013 Oct 21.
Article in English | MEDLINE | ID: mdl-23876379

ABSTRACT

The X-linked form of spondyloepiphyseal dysplasia tarda (SEDT, OMIM# 313400) is a rare osteochondrodysplasia caused by mutations in the SEDL (TRAPPC2, OMIM# 300202) gene. It is clinically characterized by disproportionate short stature, barrel-shaped chests and early development of degenerative joint disease. We report here a novel mutation in the intron 3 splice-donor site (c. 93+5G>C) segregated in an X-link pattern in a large Chinese family with SEDT. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis revealed that the mutation causes an aberrant splicing of exon 3, resulting in the elimination of 31 codons in the exon and a considerable loss function of the SEDL protein. This mutation was not detected in the 100 healthy controls. This novel mutation adds to the spectrum of previously-identified disease-causing mutations. Pre-symptomatic molecular diagnosis and prenatal diagnosis of the pregnant carriers could be helpful to families with SEDT.


Subject(s)
Chromosomes, Human, X , Genetic Diseases, X-Linked/genetics , Introns , Membrane Transport Proteins/genetics , Mutation , Osteochondrodysplasias/genetics , RNA Splice Sites , Transcription Factors/genetics , Asian People , Base Sequence , Case-Control Studies , Codon , Exons , Female , Genetic Diseases, X-Linked/ethnology , Genetic Diseases, X-Linked/pathology , Humans , Male , Molecular Sequence Data , Osteochondrodysplasias/ethnology , Osteochondrodysplasias/pathology , Pedigree , Pregnancy
12.
Genetika ; 48(9): 1105-12, 2012 Sep.
Article in Russian | MEDLINE | ID: mdl-23113339

ABSTRACT

A genetic epidemiological study has been performed in five districts of the Republic of Tatarstan, Russia: Arsky, Atninsky, Kukmorsky, Buinsky and Drozhzhanovsky raions. The total size of the population surveyed is 188 397 people. Tatars accounted for 77.13% of the population analyzed (145466 people) and were represented by two main ethnic groups: Kazan Tatars and Mishars. The medical genetic study encompassed the total population of the districts, irrespective of ethnicity, and was carried out according to the standard protocol developed in the Laboratory of Genetic Epidemiology of the Research Center for Medical Genetics of the Russian Academy of Medical Sciences. After segregation analysis, the prevalence rates of the main types of monogenic hereditary disorders (MHDs), i.e., autosomal dominant (AD), autosomal recessive (AR), and X-linked diseases, have been calculated for the total population of the five districts and for Tatars alone. The prevalence rates ofAD, AR, and X-linked diseases considerably vary in different subpopulations. The largest difference in the MHD prevalence rate has been found between the rural and urban populations. The overall prevalence rate of MHDs was one patient per 293 urban residents and populations and one patient per 134 rural residents, with a wide variation between subpopulations, from 1 : 83 people in the rural population of Atninsky raion to 1: 351 people in the town of Kukmor. Comparison of the MHD prevalence rate in Tatars with those in populations surveyed earlier has shown that the characteristics of the load of MHDs in the Tatar population are similar to those in some districts of the republics of Bashkortostan, Udmurtia, Mari El, and Chuvachia. In Russian populations of European Russia, the MHD prevalence rates are substantially lower. Correlation analysis has shown high (r = 0.5-0.9) significant correlations between the local inbreeding (a), the im index, the random inbreeding (F(ST)), and the AD and AR prevalence rates in the Tatar population. This analysis has demonstrated that genetic drift is the main population dynamic factor determining the MHD load in the Tatar population.


Subject(s)
Genetic Diseases, Inborn/epidemiology , Genetic Diseases, Inborn/genetics , Genetics, Population , Genes, Dominant , Genes, Recessive , Genetic Diseases, Inborn/ethnology , Genetic Diseases, X-Linked/epidemiology , Genetic Diseases, X-Linked/ethnology , Genetic Diseases, X-Linked/genetics , Genetic Drift , Humans , Inbreeding , Population Dynamics , Rural Population , Russia/ethnology , Urban Population
13.
Eur J Neurol ; 14(3): 305-8, 2007 Mar.
Article in English | MEDLINE | ID: mdl-17355552

ABSTRACT

Emery-Dreifuss muscular dystrophy (EDMD) is an X-linked humero-peroneal muscular dystrophy associated with contractures and cardiomyopathy. In a 90 member family, we found 11 affected male individuals, three of whom displayed areflexia and neurogenic electromyographic changes. Muscle biopsy performed in one case demonstrated type grouping suggestive of a neurogenic disorder. These three individuals and another family member, who suffers from mild, static limb weakness but is clinically and genetically unaffected by EDMD showed an abnormal incremental response of over 100% to tetanic stimulation. In contrast, one affected family member showed myopathic features on needle electromyography and no definite pathology in repetitive stimulation studies. The diagnosis of EDMD was established by demonstrating a 1712_1713insTGGGC mutation in the emerin gene. This family apparently expresses co-morbidity of EDMD with an exceptionally mild form of pre-synaptic congenital myasthenic syndrome resembling the Lambert-Eaton myasthenic syndrome (LEMS). The superimposed pre-synaptic disorder may have contributed to the development of the neurogenic features demonstrated in these patients.


Subject(s)
Genetic Predisposition to Disease/genetics , Muscle, Skeletal/physiopathology , Muscular Dystrophy, Emery-Dreifuss/ethnology , Muscular Dystrophy, Emery-Dreifuss/physiopathology , Myasthenic Syndromes, Congenital/ethnology , Myasthenic Syndromes, Congenital/physiopathology , Adolescent , Adult , Arabs/genetics , Child , Child, Preschool , Comorbidity , DNA Mutational Analysis , Disease Progression , Female , Genetic Diseases, X-Linked/ethnology , Genetic Diseases, X-Linked/genetics , Genetic Diseases, X-Linked/physiopathology , Genetic Linkage/genetics , Genetic Testing , Genotype , Humans , Male , Membrane Proteins/genetics , Middle Aged , Muscle, Skeletal/innervation , Muscle, Skeletal/pathology , Muscular Dystrophy, Emery-Dreifuss/genetics , Myasthenic Syndromes, Congenital/genetics , Nuclear Proteins/genetics , Pedigree , Phenotype
14.
J Med Assoc Thai ; 89(1): 99-105, 2006 Jan.
Article in English | MEDLINE | ID: mdl-16583589

ABSTRACT

Floppy infant syndrome (FIS) refers to a condition wherein an infant manifests generalized hypotonia since birth or in early life. It is heterogeneous and can be caused by various central nervous system disorders, neuromuscular diseases and genetic disorders. X-linked myotubular myopathy (XMTM) is a progressive congenital myopathy morphologically characterized by the presence of centrally placed nuclei in numerous muscle fibers without any other particular pathological abnormalities. Patients are frequently born with floppiness and respiratory distress. The vast majority of patients carry a truncating or missense mutation in MTM1. The authors report here a full term male baby with clinicopathological features of XMTM. The diagnosis is validated by the finding of a c. 141-144delAGAA mutation ofMTM1. To the best of the authors' knowledge, the present case is the first genetically confirmed XMTM in Thailand. A brief review of various neuromuscular disorders causing floppy infant syndrome is also included.


Subject(s)
Chromosomes, Human, X , Genetic Diseases, X-Linked/genetics , Myopathies, Structural, Congenital/genetics , Protein Tyrosine Phosphatases/genetics , Chromosome Mapping , DNA Mutational Analysis , Genetic Diseases, X-Linked/diagnosis , Genetic Diseases, X-Linked/ethnology , Humans , Infant, Newborn , Male , Myopathies, Structural, Congenital/diagnosis , Myopathies, Structural, Congenital/pathology , Pedigree , Protein Tyrosine Phosphatases, Non-Receptor , Thailand
15.
Invest Ophthalmol Vis Sci ; 46(1): 17-23, 2005 Jan.
Article in English | MEDLINE | ID: mdl-15623749

ABSTRACT

PURPOSE: A four-generation family containing eight affected males who inherited X-linked developmental lens opacity and microcornea was studied. Some members in the family had mild to moderate nonocular clinical features suggestive of Nance-Horan syndrome. The purpose of the study was to map genetically the gene in the large 57-live-member Asian-Indian pedigree. METHODS: PCR-based genotyping was performed on the X-chromosome, by using fluorescent microsatellite markers (10-cM intervals). Parametric linkage analysis was performed by using two disease models, assuming either recessive or dominant X-linked transmission by the MLINK/ILINK and FASTLINK (version 4.1P) programs (http:www.hgmp.mrc.ac.uk/; provided in the public domain by the Human Genome Mapping Project Resources Centre, Cambridge, UK). The NHS gene at the linked region was screened for mutation. RESULTS: By fine mapping, the disease gene was localized to Xp22.13. Multipoint analysis placed the peak LOD of 4.46 at DSX987. The NHS gene mapped to this region. Mutational screening in all the affected males and carrier females (heterozygous form) revealed a truncating mutation 115C-->T in exon 1, resulting in conversion of glutamine to stop codon (Q39X), but was not observed in unaffected individuals and control subjects. conclusions. A family with X-linked Nance-Horan syndrome had severe ocular, but mild to moderate nonocular, features. The clinical phenotype of the truncating mutation (Q39X) in the NHS gene suggests allelic heterogeneity at the NHS locus or the presence of modifier genes. X-linked families with cataract should be carefully examined for both ocular and nonocular features, to exclude Nance-Horan syndrome. RT-PCR analysis did not suggest nonsense-mediated mRNA decay as the possible mechanism for clinical heterogeneity.


Subject(s)
Cataract/genetics , Genetic Diseases, X-Linked/genetics , Mutation, Missense , Nuclear Proteins/genetics , Adolescent , Adult , Cataract/ethnology , Cataract/pathology , Child , Child, Preschool , Chromosomes, Human, X/genetics , Exons , Female , Genetic Diseases, X-Linked/ethnology , Genetic Diseases, X-Linked/pathology , Genetic Heterogeneity , Genetic Linkage , Genotype , Humans , India , Lod Score , Male , Membrane Proteins , Microsatellite Repeats , Middle Aged , Pedigree , Phenotype , Reverse Transcriptase Polymerase Chain Reaction
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