The green anole, Anolis carolinensis (ACA), is the model reptile for a vast array of biological disciplines. It was the first nonavian reptile to have its genome fully sequenced. During the genome project, the XX/XY system of sex chromosomes homologous to chicken chromosome 15 (GGA15) was revealed, and 106 X-linked genes were identified. We selected 38 genes located on eight scaffolds in ACA and having orthologs located on GGA15, then tested their linkage to ACA X chromosome by using comparative quantitative fluorescent real-time polymerase chain reaction applied to male and female genomic DNA. All tested genes appeared to be X-specific and not present on the Y chromosome. Assuming that all genes located on these scaffolds should be localized to the ACA X chromosome, we more than doubled the number of known X-linked genes in ACA, from 106 to 250. While demonstrating that the gene content of chromosome X in ACA and GGA15 is largely conserved, we nevertheless showed that numerous interchromosomal rearrangements had occurred since the splitting of the chicken and anole evolutionary lineages. The presence of many ACA X-specific genes localized to distinct contigs indicates that the ACA Y chromosome should be highly degenerated, having lost a large amount of its original gene content during evolution. The identification of novel genes linked to the X chromosome and absent on the Y chromosome in the model lizard species contributes to ongoing research as to the evolution of sex determination in reptiles and provides important information for future comparative and functional genomics.

• Keywords
• gene dosage, genetics of sex, lizard, qPCR, sex chromosomes, sex determination,
• MeSH
• Genetic Linkage MeSH
• Gene Dosage MeSH
• Genes, X-Linked * MeSH
• Lizards genetics   MeSH
• Conserved Sequence MeSH
• Sex Factors MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

X-linked agammaglobulinemia (XLA) was one of the first inborn errors of immunity to be described. It is caused by pathogenic variants in the gene for Bruton tyrosine kinase (BTK), which has important functions in B cell development and maturation. Recurrent bacterial infections in the first two years of life and hypogammaglobulinemia with absent B cells in male patients are the most common symptoms. A four-month-old male patient underwent surgical removal of urachus persistens complicated with recurrent scar abscesses. Hypogammaglobulinemia (IgG, IgA, and IgM), low phagocytic activity, mild neutropenia, and a normal percentage of B cells were observed in the patient's immune laboratory profile. Over time, he suffered recurrent respiratory infections (otitis media and rhinosinusitis) and developed B cell depletion, but interestingly, this was with a normalisation of IgG and IgA levels along with undetectable IgM. Molecular-genetic testing confirmed the presence of the pathogenic variant c.1843C>T in the BTK gene, which is associated with a milder phenotype of XLA. Molecular-genetic testing uncovers the variability of clinical and laboratory features of apparently well-known inherited disorders. Patients with mild "leaky" XLA may have normal levels of non-functional or oligoclonal immunoglobulins.

• Keywords
• BTK gene, Inborn error of immunity, X-linked agammaglobulinemia, atypical leaky phenotype, molecular-genetic testing,
• MeSH
• Agammaglobulinemia * genetics   diagnosis   MeSH
• Genetic Diseases, X-Linked * genetics   diagnosis   MeSH
• Genetic Testing * MeSH
• Infant MeSH
• Humans MeSH
• Agammaglobulinaemia Tyrosine Kinase * genetics   MeSH
• Check Tag
• Infant MeSH
• Humans MeSH
• Male MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH
• Names of Substances
• BTK protein, human MeSH Browser
• Agammaglobulinaemia Tyrosine Kinase * MeSH

BACKGROUND: Many centers of assisted reproduction in the Czech Republic offer preimplantation genetic diagnosis with fluorescent in situ hybridization (FISH) to couples requiring preimplantation genetic diagnosis (PGD) of X-linked diseases. However, this process results in discarding all male embryos and is not able to distinguish a carrier or healthy female embryo in X-linked recessive disorders. OBJECTIVES: The main aim of this study was to summarize a six-year period of PGD of X-linked monogenic diseases using indirect linkage analysis. METHODS AND RESULTS: We wanted to accentuate the advantage indirect analysis of PGD using multiple displacement amplification (MDA) followed by short tandem repeat (STR) analysis. We present forty-six PGD cycles, including pre-case haplotyping (PGH) panel, for fifteen X-linked diseases. Embryo transfer was made thirty-eight times and gravidity was confirmed in thirteen female probands with a success rate of pregnancy calculated at 42 %. CONCLUSIONS: PGD procedure using MDA amplification followed by STR analysis provides help in identifying genetic defects within embryos prior to implantation. The reliability of the method was also supported by high pregnancy rate compared to other publications, which commonly achieved a 30-35 % success rate (Tab. 2, Fig. 1, Ref. 33).

• Keywords
• X-linked inheritance, haplotype analysis., indirect diagnosis, single gene mutation,
• MeSH
• Adult MeSH
• Fertilization in Vitro * MeSH
• Genetic Linkage * MeSH
• Genetic Diseases, X-Linked diagnosis   genetics   prevention & control   MeSH
• Haplotypes MeSH
• Cohort Studies MeSH
• Humans MeSH
• Microsatellite Repeats MeSH
• Mutation MeSH
• Preimplantation Diagnosis methods   MeSH
• Embryo Transfer * MeSH
• Reproducibility of Results MeSH
• Retrospective Studies MeSH
• Nucleic Acid Amplification Techniques MeSH
• Pregnancy MeSH
• Pregnancy Rate MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Male MeSH
• Pregnancy MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Study MeSH
• Geographicals
• Czech Republic MeSH

Chondrodysplasia punctata represents clinically and genetically a heterogeneous group of disorders characterized by the presence of multiple congenital anomalies and stippled epiphyses. We present clinical course of the disease and the results of metabolic, X-ray and molecular analyses in 19-months old girl with X-linked dominant chondrodysplasia punctata with intrauterine growth retardation, craniofacial dysmorphy, cataracts, cutaneous anomalies including ichthyosis, asymmetric rhizomesomelic shortness of the limbs, deformity of the spine, club foot, polydactyly, syndactyly, epiphyseal stippling and low cholesterol (2.29 mmol/l). Spectrophotometric analysis revealed the presence of abnormal pattern of cholesterol precursors in blood. The increased level of 8-dehydrocholesterol (42.2 micromol/l, controls < 1) and 7-dehydrocholesterol (25.5 micromol/l, controls < 1) recognised with GC/MS suggested an endogenous defect of cholesterol biosynthesis. The diagnosis of X-linked dominant chondrodysplasia punctata (CDPX2) was confirmed by the molecular analysis. Sequencing of the EBP gene encoding for 3beta-hydroxysteroid-delta8,delta7-isomerase revealed the presence of "de novo" heterozygous mutation c.327C>T (p.Arg110Stop). High cholesterol diet normalized cholesterol level (3.28 mmol/l) but it had no influence on the unfavourable prognosis of the disease. Low level of cholesterol with abnormal sterol profile in a child with congenital development anomalies represent an important laboratory marker suggesting an inherited defect of cholesterol biosynthesis.

• MeSH
• Cholesterol biosynthesis   MeSH
• Chondrodysplasia Punctata congenital   genetics   metabolism   MeSH
• Genetic Diseases, X-Linked * MeSH
• Infant MeSH
• Humans MeSH
• Lipid Metabolism, Inborn Errors genetics   MeSH
• Check Tag
• Infant MeSH
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Cholesterol MeSH

One of the reproductive barriers between diverging populations during formation of a new species is the sterility of their hybrids. The Prdm9-driven hybrid male sterility of Mus musculus musculus × Mus musculus domesticus hybrids depends on the interaction between PRDM9, a histone methyltransferase that determines the positions of meiotic recombination hotspots, and an as yet unknown X-linked genetic factor within the Hybrid sterility X2 (Hstx2) locus. Here, we report that the Mir465 microRNA (miRNA) gene cluster is the predicted Hstx2 hybrid sterility factor. We show that removal of the Mir465 genes restores the fertility of sterile hybrids and improves meiotic synapsis of homologous chromosomes. Mir465 knockout also restores spermatogenesis in sterile chromosomal translocation carriers, demonstrating that Mir465 acts as a meiotic checkpoint that can be activated independently of Prdm9 intersubspecific incompatibility. Furthermore, the Mir465 knockout increases the global recombination rate in hybrids and in parental Mus m. domesticus mice. This demonstrates that Mir465 is responsible for the phenotypes of the two overlapping genetic loci, the Hstx2 engaged in fertility of hybrids and the Meiotic recombination 1 (Meir1) controlling the recombination rate. The finding of enlarged Mir465 clusters in all European Mus m. musculus samples tested and the identification of differentially expressed targets suggest that the reproductive barrier between the two subspecies is sensitive to copy number variation of Mir465 genes. Together, the underdominant interaction between Prdm9 and Mir465 provides a rare example of Dobzhansky-Muller incompatibility in hybrids of closely related species, making it accessible for further analysis at the molecular level.

• Keywords
• PRDM9, Tiprl, meiosis, speciation,
• MeSH
• Genes, X-Linked * MeSH
• Histone-Lysine N-Methyltransferase * genetics   metabolism   MeSH
• Hybridization, Genetic MeSH
• Meiosis * genetics   MeSH
• MicroRNAs * genetics   metabolism   MeSH
• Multigene Family MeSH
• Infertility, Male * genetics   MeSH
• Mice MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Histone-Lysine N-Methyltransferase * MeSH
• MicroRNAs * MeSH
• prdm9 protein, mouse MeSH Browser

BACKGROUND: Hypertrophic cardiomyopathy with severe left ventricular diastolic dysfunction has been associated with marked exercise intolerance and poor prognosis. However, molecular pathogenesis of this phenotype remains unexplained in a large proportion of cases. METHODS AND RESULTS: We performed whole exome sequencing as an initial genetic test in a large Czech family with 3 males affected by nonobstructive hypertrophic cardiomyopathy with severe left ventricular diastolic dysfunction in end-stage disease. A novel frameshift mutation of four-and-a-half LIM domain 1 gene (FHL1) (c.599_600insT; p.F200fs32X) was detected in these individuals. The mutation does not affect transcription, splicing, and stability of FHL1 mRNA and results in production of truncated FHL1 protein, which is contrary to heart tissue homogenate not detectable in frozen tissue sections of myocardial biopsy of affected males. The identified mutation cosegregated also with abnormal ECG and with 1 case of apical hypertrophic cardiomyopathy in heterozygous females. Although skeletal muscle involvement is a common finding in FHL1-related diseases, we could exclude myopathy in all mutation carriers. CONCLUSIONS: We identified a novel FHL1 mutation causing isolated hypertrophic cardiomyopathy with X-chromosomal inheritance.

• Keywords
• cardiomyopathy, hypertrophic, exome, heart failure, diastolic,
• MeSH
• Adult MeSH
• Electrocardiography MeSH
• Microscopy, Electron MeSH
• Genetic Predisposition to Disease genetics   MeSH
• Genes, X-Linked genetics   MeSH
• Cardiomyopathy, Hypertrophic genetics   metabolism   physiopathology   MeSH
• Immunohistochemistry MeSH
• Intracellular Signaling Peptides and Proteins genetics   metabolism   MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Mutation * MeSH
• Myocardium metabolism   pathology   ultrastructure   MeSH
• Reverse Transcriptase Polymerase Chain Reaction MeSH
• LIM Domain Proteins genetics   metabolism   MeSH
• Pedigree MeSH
• Aged, 80 and over MeSH
• Muscle Proteins genetics   metabolism   MeSH
• Family Health MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• FHL1 protein, human MeSH Browser
• Intracellular Signaling Peptides and Proteins MeSH
• LIM Domain Proteins MeSH
• Muscle Proteins MeSH

BACKGROUND: X-linked agammaglobulinemia is an inherited immunodeficiency recognized since 1952. In spite of seven decades of experience, there is still a limited understanding of regional differences in presentation and complications. This study was designed by the Primary Immunodeficiencies Committee of the World Allergy Organization to better understand regional needs, challenges and unique patient features. METHODS: A survey instrument was designed by the Primary Immunodeficiencies Committee of the World Allergy Organization to collect both structured and semi-structured data on X-linked agammaglobulinemia. The survey was sent to 54 centers around the world chosen on the basis of World Allergy Organization participation and/or registration in the European Society for Immunodeficiencies. There were 40 centers that responded, comprising 32 countries. RESULTS: This study reports on 783 patients from 40 centers around the world. Problems with diagnosis are highlighted by the reported delays in diagnosis>24 months in 34% of patients and the lack of genetic studies in 39% of centers Two infections exhibited regional variation. Vaccine-associated paralytic poliomyelitis was seen only in countries with live polio vaccination and two centers reported mycobacteria. High rates of morbidity were reported. Acute and chronic lung diseases accounted for 41% of the deaths. Unusual complications such as inflammatory bowel disease and large granular lymphocyte disease, among others were specifically enumerated, and while individually uncommon, they were collectively seen in 20.3% of patients. These data suggest that a broad range of both inflammatory, infectious, and autoimmune conditions can occur in patients. The breadth of complications and lack of data on management subsequently appeared as a significant challenge reported by centers. Survival above 20 years of age was lowest in Africa (22%) and reached above 70% in Australia, Europe and the Americas. Centers were asked to report their challenges and responses (n = 116) emphasized the difficulties in access to immunoglobulin products (16%) and reflected the ongoing need for education of both patients and referring physicians. CONCLUSIONS: This is the largest study of patients with X-linked agammaglobulinemia and emphasizes the continued morbidity and mortality of XLA despite progress in diagnosis and treatment. It presents a world view of the successes and challenges for patients and physicians alike. A pivotal finding is the need for education of physicians regarding typical symptoms suggesting a possible diagnosis of X-linked agammaglobulinemia and sharing of best practices for the less common complications.

• Keywords
• Agammaglobulinemia, Autoimmunity, CLD, Chronic lung disease, FH, Family history, GI, Gastrointestinal, Immunoglobulin, Infection, JIA, juvenile idiopathic arthritis, Outcomes, SCIG, Subcutaneous immunoglobulin, Therapy, VAPP, Vaccine associated paralytic poliomyelitis, XLA, XLA, X-linked agammaglobulinemia,
• Publication type
• Journal Article MeSH

X-ALD is a neurological disorder associated with inherited defects in the ABCD1 (ALD) gene located on Xq28 and with impaired peroxisomal very long-chain fatty acid beta-oxidation. We examined the ABCD1 gene in probands from 11 unrelated X-ALD Czech and Slovak families by the direct sequencing of cDNA or genomic PCR products. In 10 families there were 10 different mutations, eight of which were novel. The spectrum of mutations consists of six point mutations, three microdeletions (1bp, 2bp, 4 bp), and one large deletion (229bp). In the 11th family we detected two novel single-base pair substitutions in exon 1 (c.38 A>C and c.649 A>G), both causing amino acid exchanges (N13T and K217E). Expression studies revealed that only K217E is a deleterious mutation, because a plasmid encoding ALDP with K217E was ineffective in the restoration of defective beta-oxidation in X-ALD fibroblasts. The N13T amino acid exchange, on the other hand, did not affect ALDP function. Thus, N13T represents the first polymorphism causing an amino acid exchange in the ABCD1 gene. As this polymorphism was observed neither in 100 control alleles nor in 300 X-ALD patients who have been sequenced so far world-wide, it seems to be very rare or unique. Two additional novel polymorphisms were found by the sequencing of the ABCD1 gene from our patients: c.-59 C/T in the 5'untranslated region and c.2019 C/T (F673F) in exon 10. The frequencies of these two polymorphisms, were 11/150 and 2/150 control alleles, respectively.

• MeSH
• 5' Untranslated Regions genetics   MeSH
• ATP Binding Cassette Transporter, Subfamily D, Member 1 MeSH
• ATP-Binding Cassette Transporters chemistry   genetics   MeSH
• Adrenoleukodystrophy genetics   MeSH
• Alleles MeSH
• Amino Acid Motifs MeSH
• X Chromosome genetics   MeSH
• Child MeSH
• Adult MeSH
• Exons genetics   MeSH
• Phenotype MeSH
• Genetic Linkage genetics   MeSH
• Polymorphism, Single Nucleotide genetics   MeSH
• Conserved Sequence MeSH
• Palmitic Acid metabolism   MeSH
• Humans MeSH
• Fatty Acids metabolism   MeSH
• Membrane Proteins chemistry   genetics   MeSH
• Mutation, Missense genetics   MeSH
• Adolescent MeSH
• Molecular Sequence Data MeSH
• DNA Mutational Analysis MeSH
• Oxidation-Reduction MeSH
• Polymorphism, Genetic genetics   MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Geographicals
• Czech Republic MeSH
• Slovakia MeSH
• Names of Substances
• 5' Untranslated Regions MeSH
• ATP Binding Cassette Transporter, Subfamily D, Member 1 MeSH
• ATP-Binding Cassette Transporters MeSH
• ABCD1 protein, human MeSH Browser
• Palmitic Acid MeSH
• lignoceric acid MeSH Browser
• Fatty Acids MeSH
• Membrane Proteins MeSH

Most pleurodont lizard families (anoles, iguanas and their relatives), with the exception of the basilisks and casquehead lizards (family Corytophanidae), share homologous XX/XY sex chromosomes, syntenic with chicken chromosome 15. Here, we used a suite of methods (i.e. RADseq, RNAseq and qPCR) to identify corytophanid sex chromosomes for the first time. We reveal that all examined corytophanid species have partially degenerated XX/XY sex chromosomes, syntenic with chicken chromosome 17. Transcriptomic analyses showed that the expression of X-linked genes in the corytophanid, Basiliscus vittatus, is not balanced between the sexes, which is rather exceptional under male heterogamety, and unlike the dosage-balanced sex chromosomes in other well-studied XX/XY systems, including the green anole, Anolis carolinensis. Corytophanid sex chromosomes may represent a rare example of a turnover away from stable, differentiated sex chromosomes. However, because of poor phylogenetic resolution among pleurodont families, we cannot reject the alternative hypothesis that corytophanid sex chromosomes evolved independently from an unknown ancestral system.

• Keywords
• RADseq, RNAseq, dosage compensation, reptiles, sex chromosomes, sex determination,
• MeSH
• Phylogeny MeSH
• Genes, X-Linked MeSH
• Lizards * MeSH
• Iguanas * MeSH
• Evolution, Molecular MeSH
• Sex Chromosomes MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH

PURPOSE: To describe the genotype-phenotype correlation and serial observations in a five-generation Czech family with X-linked retinitis pigmentosa (XLRP) associated with severe visual impairment in women. METHODS: Comprehensive ophthalmological examination including spectral domain optical coherence tomography (SD-OCT) was performed. Based on the pedigree structure and women being severely affected, autosomal dominant inheritance was suspected, and screening for known mutations by genotyping microarray was performed. Subsequently, direct sequencing of ORF15 RPGR was undertaken. RESULTS: Eighteen family members (nine women and nine men) were examined. A pathogenic variant, c.2543del in ORF15 of RPGR, was found to segregate with disease. The oldest woman and her two sisters had no perception of light in their sixth decade. Four women and five men had signs and symptoms of typical XLRP, including moderate to high myopia. Three other women also had moderate to high myopia and myopic astigmatism but without the presence of bone spicule-like formation. Severe disruption of macular architecture on SD-OCT was equally common in both sexes. Only one 32-year-old female carrier had clinically normal findings. Subfoveal choroidal thickness was decreased in all affected men and in all female carriers, except the only carrier with a normal fundus examination. CONCLUSIONS: The c.2543del mutation in ORF15 of RPGR is associated with a severe phenotype in the women in this family. The presence of a significant myopic refractive error, in the absence of male-to-male transmission, may be indicative of X-linked inheritance. Measurements of choroidal thickness may help in clinically identifying carrier status.

• MeSH
• Choroid metabolism   pathology   MeSH
• Child MeSH
• Genes, Dominant MeSH
• Adult MeSH
• Genes, X-Linked * MeSH
• Heterozygote MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Molecular Sequence Data MeSH
• Eye Proteins genetics   MeSH
• Tomography, Optical Coherence MeSH
• Open Reading Frames MeSH
• Retina metabolism   pathology   MeSH
• Retinitis Pigmentosa genetics   pathology   MeSH
• Pedigree MeSH
• Base Sequence * MeSH
• Sequence Deletion * MeSH
• Aged MeSH
• Sex Factors MeSH
• Severity of Illness Index MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Eye Proteins MeSH
• RPGR protein, human MeSH Browser