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PubMed2006

Analysis of sugarcane mosaic virus resistance in maize in an isogenic dihybrid crossing scheme and implications for breeding potyvirus-resistant maize hybrids.

The gene action of 2 sugarcane mosaic virus (SCMV) resistance loci in maize, Scmv1 and Scmv2, was evaluated for potyvirus resistance in an isogenic background. All 4 homozygous and 5 heterozygous isogenic genotypes were produced for introgressions of the resistant donor (FAP1360A) alleles at both loci into the susceptible parent (F7) genetic background using simple sequence repeat markers. For SCMV and maize dwarf mosaic virus (MDMV), virus symptoms appeared rapidly in the 3 homozygous genotypes, with susceptibility alleles fixed at 1 or both loci. Although the 9 isogenic genotypes revealed a high level of resistance to Zea mosaic virus (ZeMV), the same 3 homozygous genotypes were only partially resistant. This indicates that 1 resistance gene alone is not sufficient for complete resistance against SCMV, MDMV, and ZeMV. Scmv1 showed strong early and complete dominant gene action to SCMV, but it gradually became partially dominant. Scmv2 was not detected at the beginning, showing dominant gene action initially and additive gene action at later stages. Both genes interacted epistatically (for a high level of resistance, at least 1 resistance allele at each of both loci is required). This implies that double heterozygotes at the 2 loci are promising for producing SCMVresistant hybrids. Results are discussed with respect to prospects for isolation of SCMV and MDMV resistance genes.

Breeding↗
PubMed1998

Chromosomal mosaicisms during prenatal diagnosis.

Chromosomal mosaicism during prenatal diagnosis has been a major concern. Nondisjunctional events can lead to mosaicism in a number of ways, including failure of chromosomal pairing, failure to separate, anaphase lag and abnormal segregation. We provide a concise review on various types of mosaicism with their clinical significance.

Amniocentesis↗
PubMedDate not supplied

Extreme elevation of maternal serum alpha-fetoprotein associated with mosaic trisomy 8 in a liveborn.

Constitutional mosaic trisomy 8 has been associated with syndromic dysmorphology, corneal opacities, leukemias, and trophoblastic disease. However, abnormal maternal serum alpha-fetoprotein (MSAFP) has not been reported in association with mosaic trisomy 8. Our case first presented for evaluation of an extremely elevated MSAFP with mild elevation of MShCG in an otherwise normal pregnancy: MSAFP 13.89 MoM, MShCG 3.57 MoM, and MSuE3 1.04 MoM. Fetal dysmorphism was limited to bilateral pyelectasis and a prominent third ventricle. Spontaneous labor at 38 weeks resulted in the birth of a 3,570-gram AGA male with APGARs 7(1)/8(5). The neonate had facial asymmetry, 5th finger clinodactyly, 2-3 toe syndactyly, undescended testicle, abnormal prepuce, and mild pyelectasis. CT scan revealed hypoplasia of the corpus callosum, while echocardiography demonstrated bicuspid aortic valve, and the neonatal karyotype (blood) returned 46,XY/47,XY+8. Evaluation at 3 months revealed more prominent facial asymmetry, plagiocephaly, plantar creases, descent of the testis, and mild developmental delay. Review of the literature does not include any previously reported maternal serum alpha-fetoprotein aberrations in mosaic trisomy 8.

Adult↗
PubMed2000

Familial mosaicism of del(Y) and inv del(Y).

Molecular cytogenetic investigation of a male proband showing oligozoospermia (OAT I-II degrees ) has led to the detection of a Y-chromosome mosaicism. This mosaicism consists of a deleted Y chromosome with deletion of most of the long-arm heterochromatin, including the PAR2, del(Y), and a Y chromosome, which, in addition to that deletion, shows a paracentric long-arm inversion, inv del(Y), with breakpoints in the DAZ gene cluster in deletion interval 6 and within the remainder of the long-arm heterochromatin of the Y. The Y mosaicism is not confined to the sterile proband but is also detected in both his father and his fertile brother. Interestingly, the percentage of inv del(Y) is highest (80%) in the proband showing oligozoospermia.

Adult↗
PubMed2001

Unusual chromosomal mosaicism as a cause of mental retardation and congenital malformations in a familial reciprocal translocation carrier, t(17;22)(q24.2;q11.23).

Familial reciprocal translocations are generally without phenotypic effect, although there is some evidence for a small excess of mental retardation and congenital malformations (MR/CM) in children carrying familial reciprocal translocations. Possible mechanisms whereby such translocations could have a phenotypic effect include cryptic unbalanced rearrangements, uniparental disomy, and disruption of putative genes at the breakpoints, unmasking recessive alleles on the normal homologs. Mosaicism for a supernumerary derivative chromosome in a carrier of a familial reciprocal translocation has not yet been described. We report a boy presenting with MR/CM and a familial reciprocal translocation, t(17;22)(q24.2;q11.23), inherited from the mother. Cytogenetic analysis of peripheral blood lymphocytes showed a balanced karyotype in all 32 analyzed metaphase spreads. Molecular genetic analysis was consistent with biparental origin of the normal homologs. In metaphase spreads from skin fibroblasts a supernumerary chromosome was found in all 24 cells analyzed and could be identified as der(22)t(17;22)(q24.2;q11.23). Several possible segregation modes at meiosis I followed by meiosis II or postzygotic nondisjunction of the der(22) might have led to this unusual chromosomal mosaicism. We propose hidden mosaicism as a possible cause for MR/CM in patients who apparently carry a balanced familial reciprocal translocation.

Abnormalities, Multiple↗
PubMedDate not supplied

Prenatal diagnosis of trisomy 2 mosaicism: a case report.

We report a case of trisomy 2 mosaicism detected upon amniocentesis in a woman with advanced maternal age. A mos 47,XY,+2(4)/46,XY(21) karyotype was revealed using standard GTG banding. There were no pathological sonographic findings and the fetal size was normal for gestational age at 16th week. The use of serial high-resolution ultrasound examination of the fetus to detect major abnormalities was offered as an option to the parents who, however, decided for termination of the pregnancy. Fetal autopsy did not reveal any malformations. Trisomy 2 mosaicism is associated with variable phenotypic abnormalities without a specific pattern, intrauterine growth restriction, fetal demise or stillbirth. The rarity of trisomy-2 mosaicism in prenatal diagnosis, as well as the increased risk of an abnormal outcome makes the diagnostic approach and genetic counseling difficult.

Adult↗
PubMed1976

Trisomy 13 mosaic presenting as cleft lip and palate.

A mosaic trisomy 13 presenting as a case of cleft lip and palate in the newborn is described. However, when the child was admitted to hospital at the age of 6 weeks because of failure to gain weight and a malformation of the great vessels was demonstrated, cytogenetic studies were carried out. The diagnosis of mosaic trisomy 13 (90% normal, 10% trisomic) was established from a leukocyte culture. Since, occasionally, mosaic trisomy 13 may mimic cleft lip and palate in the newborn, cytogenetic studies are indicated in the presence of any additional anomaly.

Chromosomes, Human, 13-15↗
PubMed2004

Recurrent third-trimester fetal loss and maternal mosaicism for long-QT syndrome.

BACKGROUND: The importance of germ-line mosaicism in genetic disease is probably underestimated, even though recent studies indicate that it may be involved in 10% to 20% of apparently de novo cases of several dominantly inherited genetic diseases. METHODS AND RESULTS: We describe here a case of repeated germ-line transmission of a severe form of long-QT syndrome (LQTS) from an asymptomatic mother with mosaicism for a mutation in the cardiac sodium channel, SCN5A. A male infant was diagnosed with ventricular arrhythmias and cardiac decompensation in utero at 28 weeks and with LQTS after birth, ultimately requiring cardiac transplantation for control of ventricular tachycardia. The mother had no ECG abnormalities, but her only previous pregnancy had ended in stillbirth with evidence of cardiac decompensation at 7 months' gestation. A third pregnancy also ended in stillbirth at 7 months, again with nonimmune fetal hydrops. The surviving infant was found to have a heterozygous mutation in SCN5A (R1623Q), previously reported as a de novo mutation causing neonatal ventricular arrhythmia and LQTS. Initial studies of the mother detected no genetic abnormality, but a sensitive restriction enzyme-based assay identified a small (8% to 10%) percentage of cells harboring the mutation in her blood, skin, and buccal mucosa. Cord blood from the third fetus also harbored the mutant allele, suggesting that all 3 cases of late-term fetal distress resulted from germ-line transfer of the LQTS-associated mutation. CONCLUSIONS: Recurrent late-term fetal loss or sudden infant death can result from unsuspected parental mosaicism for LQTS-associated mutations, with important implications for genetic counseling.

Adult↗
PubMed2003

Second-site mutation in the Wiskott-Aldrich syndrome (WAS) protein gene causes somatic mosaicism in two WAS siblings.

Revertant mosaicism due to true back mutations or second-site mutations has been identified in several inherited disorders. The occurrence of revertants is considered rare, and the underlying genetic mechanisms remain mostly unknown. Here we describe somatic mosaicism in two brothers affected with Wiskott-Aldrich syndrome (WAS). The original mutation causing disease in this family is a single base insertion (1305insG) in the WAS protein (WASP) gene, which results in frameshift and abrogates protein expression. Both patients, however, showed expression of WASP in a fraction of their T cells that were demonstrated to carry a second-site mutation causing the deletion of 19 nucleotides from nucleotide 1299 to 1316. This deletion abrogated the effects of the original mutation and restored the WASP reading frame. In vitro expression studies indicated that mutant protein encoded by the second-site mutation was expressed and functional, since it was able to bind to cellular partners and mediate T cell receptor/CD3 downregulation. These observations were consistent with evidence of in vivo selective advantage of WASP-expressing lymphocytes. Molecular analysis revealed that the sequence surrounding the deletion contained two 4-bp direct repeats and that a hairpin structure could be formed by five GC pairs within the deleted fragment. These findings strongly suggest that slipped mispairing was the cause of this second-site mutation and that selective accumulation of WASP-expressing T lymphocytes led to revertant mosaicism in these patients.

Adolescent↗
PubMed1999

Revertant mosaicism: partial correction of a germ-line mutation in COL17A1 by a frame-restoring mutation.

Generalized atrophic benign epidermolysis bullosa is an autosomal recessive subepidermal blistering disease typified by null mutations in COL17A1. In 1 large kindred, affected individuals were homozygous for a 2-bp deletion in COL17A1, 4003delTC, which resulted in a downstream premature termination codon, nonsense-mediated mRNA decay, and abrogation of type XVII collagen synthesis. Interestingly, 1 of these patients, although phenotypically identical to her affected siblings, showed focal expression of type XVII collagen in epidermal basement membrane in a pattern suggestive of revertant mosaicism. When studies of randomly obtained epidermal, oromucosal, and peripheral blood cells failed to identify the genetic basis of this apparent mosaicism, microscopic subpopulations of potentially revertant epidermal cells (i.e., those overlying basement membrane containing type XVII collagen) were selectively isolated using laser capture microdissection. Analysis of DNA and RNA from these cells revealed a second mutation, 4080insGG, on 1 allele of COL17A1. This 2-bp insertion corrected the reading frame just proximal to the premature termination codon, countered nonsense-mediated mRNA decay, and allowed protein production by patient keratinocytes in vivo and in vitro. These studies elucidate the molecular basis of a novel form of revertant mosaicism in humans.

Alleles↗
PubMed2004

Multiple patients with revertant mosaicism in a single Wiskott-Aldrich syndrome family.

We previously reported on a 43-year-old patient with Wiskott-Aldrich syndrome (WAS) who experienced progressive clinical improvement and revertant T-cell mosaicism. Deletion of the disease-causing 6-bp insertion was hypothesized to have occurred by DNA polymerase slippage. We now describe 2 additional patients from the same family who also had revertant T lymphocytes that showed selective in vivo advantage. Somatic mosaicism was demonstrated on leukocytes cryopreserved in the first patient when he was 22 years old, 11 years before his death from kidney failure. The second patient is now 16 years old, has a moderate clinical phenotype, and developed revertant cells after the age of 14 years. These results support DNA polymerase slippage as a common underlying mechanism, and they indicate that T-cell mosaicism may have different clinical effects in WAS.

Adolescent↗
PubMed2004

Neonatal diabetes mellitus and neonatal polycystic, dysplastic kidneys: Phenotypically discordant recurrence of a mutation in the hepatocyte nuclear factor-1beta gene due to germline mosaicism.

Mutations in the gene coding for hepatocyte nuclear factor-1beta (HNF-1beta) have been known to cause a form of maturity-onset diabetes of the young (MODY5), which is usually characterized by dominantly inherited adolescence-onset diabetes mellitus associated with renal cysts. This report, however, describes recurrence of a novel missense mutation in the HNF-1beta gene, S148W (C443G), in two sibs, one with neonatal diabetes mellitus and the other with neonatal polycystic, dysplastic kidneys leading to early renal failure. The former patient had only a few small renal cysts with normal renal functions, and the latter had only a transient episode of hyperglycemia, which resolved spontaneously. Interestingly, both parents were clinically unaffected, and PCR restriction fragment length polymorphism analysis showed that the mother was a low-level mosaic of normal and mutant HNF-1beta, which suggested that the recurrence was caused by germline mosaicism. This is the first report of permanent neonatal diabetes mellitus caused by a mutation of the HNF-1beta gene as well as the first report of germline mosaicism of this gene. In addition, the two cases described here show that additional factors, genetic or environmental, can have a significant influence on the phenotypic expression of HNF-1beta mutations.

Child↗
PubMed2005

Somatic and germline mosaicism for a mutation of the PHEX gene can lead to genetic transmission of X-linked hypophosphatemic rickets that mimics an autosomal dominant trait.

CONTEXT: Familial hypophosphatemic rickets is usually transmitted as an X-linked dominant disorder (XLH), although autosomal dominant forms have also been observed. Genetic studies of these disorders have identified mutations in PHEX and FGF23 as the causes of X-linked dominant disorder and autosomal dominant forms, respectively. OBJECTIVE: The objective of the study was to describe the molecular genetic findings in a family affected by hypophosphatemic rickets with presumed autosomal dominant inheritance. PATIENTS: We studied a family in which the father and the elder of his two daughters, but not the second daughter, were affected by hypophosphatemic rickets. The pedigree interpretation of the family suggested that genetic transmission of the disorder occurred as an autosomal dominant trait. METHODS AND RESULTS: Direct nucleotide sequencing of FGF23 and PHEX revealed that the elder daughter was heterozygous for an R567X mutation in PHEX, rather than FGF23, suggesting that the genetic transmission occurred as an X-linked dominant trait. Unexpectedly, the father was heterozygous for this mutation. Single-nucleotide primer extension and denaturing HPLC analysis of the father using DNA from single hair roots revealed that he was a somatic mosaic for the mutation. Haplotype analysis confirmed that the father transmitted the genotypes for 18 markers on the X chromosome equally to his two daughters. The fact that the father transmitted the mutation to only one of his two daughters indicated that he was a germline mosaic for the mutation. CONCLUSIONS: Somatic and germline mosaicism for an X-linked dominant mutation in PHEX may mimic autosomal dominant inheritance.

Adult↗
PubMed2006

Mosaicism of a thyroid hormone receptor-beta gene mutation in resistance to thyroid hormone.

CONTEXT: Heterozygous mutations in thyroid hormone receptor-beta (TRbeta) gene are the cause of resistance to thyroid hormone (RTH) in more than 85% of families having the syndrome. In 23% of the families, TRbeta gene mutations occur de novo. Of the 141 families with RTH investigated by us, 21 (15%) had no TRbeta gene mutations detectable by sequencing from genomic DNA (gDNA) or cDNA (non-TR RTH). OBJECTIVE: The objective of the study was to investigate the genotype of a family with RTH and correlate it to the phenotype. DESIGN: The DNA was isolated from different tissues, and the sequence of the TRbeta gene was determined. Clinical studies involved the administration of incremental doses of T(3). SETTING: The study was conducted at a referral pediatric endocrinology clinic in Turkey and an academic medical center in the United States. MAIN OUTCOME AND MEASURES: Measurement included markers of thyroid hormone action and sequencing of TRbeta revealing a R338W mutation. Patients and Family: We studied two siblings with short stature, panic disorder, psychosis, and high free iodothyronine concentrations with nonsuppressed TSH and their father with similar thyroid function tests without growth or psychiatric abnormalities. RESULTS: Direct sequencing of gDNA obtained from the father's leukocytes, buccal mucosa cells, and prostate tissue showed less amplification of the mutant allele (R338W) than the normal allele as confirmed by PCR/restriction fragment length polymorphism analysis. No sequence abnormalities were detected in gDNA from fibroblasts. Similar results were found in mRNA from the leukocytes and fibroblasts. The sensitivity of various tissues to thyroid hormone was not uniform. The progeny had equal amounts of mutant and wild-type gDNA in leukocytes and skin. CONCLUSIONS: The father has a mosaicism for the R338W mutation as it was present in some cell lineages, including his germline, because it was transferred to his children but not in fibroblasts. This indicates that the mutation occurred de novo in early embryonic life. Here is the first report of mosaicism in RTH. The possibility of mosaicism should be considered in subjects with RTH without apparent mutations in the TRbeta gene.

Adult↗
PubMed1997

Mosaicism due to a somatic mutation of the androgen receptor gene determines phenotype in androgen insensitivity syndrome.

Premature stop codons of the human androgen receptor (AR) gene are usually associated with a complete androgen insensitivity syndrome. We, however, identified an adult patient with a 46,XY karyotype carrying a premature stop codon in exon 1 of the AR gene presenting with signs of partial virilization: pubic hair Tanner stage 4 and clitoral enlargement. No other family members were affected. A point mutation at codon position 172 of the AR gene was detected that replaced the original TTA (Leu) with a premature stop codon TGA (opal). Careful examination of the sequencing gel, however, also identified a wild-type allele, indicating a mosaicism. In addition, elimination of the unique AflII recognition site induced by the mutation was incomplete, thus confirming the coexistence of mutant and wild-type AR alleles in the patient. Normal R1881 binding and a normal 110/112-kDa AR doublet in Western immunoblots consolidated the molecular genetic data by demonstrating the expression of the wild-type AR in the patient's genital skin fibroblasts. Transfection analysis revealed that only relatively high plasmid concentrations carrying the mutated AR complementary DNA lead to expression of a shortened AR due to downstream reinitiation at methionine 189. Thus, reinitiation does not play a role in the presentation of the phenotype; rather, the partial virilization is caused by the expression of the wild-type AR due to a somatic mosaic. We conclude that somatic mosaicism of the AR gene can represent a substantial factor for the individual phenotype by shifting it to a higher degree of virilization than expected from the genotype of the mutant allele alone.

Adult↗
PubMed2003

Investigating C. elegans development through mosaic analysis.

The analysis of genetically mosaic worms, in which some cells carry a wild-type gene and others are homozygous mutant, can reveal where in the animal a gene acts to prevent the appearance of a mutant phenotype. In this primer article, we describe how Caenorhabditis elegans genetic mosaics are generated, identified and analyzed, and we discuss examples in which the analysis of mosaic worms has provided important information about the development of this organism.

Animals↗
PubMed1987

Change of mosaic pattern by androgens during prostatic bud formation in XTfm/X+ heterozygous female mice.

The testicular feminization (Tfm) gene, which is characterized by a deficiency in androgen receptors, is located on the X-chromosome. Using steroid autoradiography, the mosaicism of the Tfm gene has been demonstrated in the androgen target tissues of XTfm/X+ heterozygous female mouse fetuses and the effects of androgens on the mosaic pattern analysed. In the mesenchyme of urogenital sinuses of wild-type female fetuses (X+/X+), more than 95% of the cells were androgen-receptor positive (labelled with [3H]testosterone) while in that of heterozygous fetuses (XTfm/X+), only half of the cells were receptor positive (Tfm gene inactive), and receptor-positive cells and -negative cells formed small irregular patches. When the heterozygous sinuses were cultured in vitro in the presence of androgens, the sinuses underwent male sexual development and formed epithelial buds (prostate gland rudiments) projecting into the surrounding mesenchyme. Autoradiographic analysis revealed that the mosaicism of the mesenchyme disappeared around the developing epithelial buds: almost all the mesenchymal cells in close vicinity to the buds were receptor positive while in the outer layers receptor-positive and -negative cells coexisted. The proportion of receptor-positive cells was greatly increased in the mesenchyme beneath the non-budding area of the sinus epithelium. This androgen-induced increase was observed before the onset of bud formation. The results obtained in the thymidine incorporation experiments suggest that the increase of receptor-positive cells beneath the sinus epithelium might be explained by the migratory behaviour of the androgen-incorporating cells rather than by their selective proliferation.

Androgen-Insensitivity Syndrome↗
PubMed1992

Pentasomy X mosaic in two adult sisters with diabetes mellitus.

Pentasomy X mosaic in two adult sisters with non-insulin dependent diabetes mellitus is described. The younger sister had schizophrenia, and both were mentally retarded, but no apparent somatic abnormalities were found. Chromosome analyses revealed karyotype 45,X/46,XX/47,XXX/48,XXXX/49,XXXXX mosaic with a low frequency of aneuploidy on cultured peripheral lymphocytes and 46,XX on cultured skin fibroblasts in both sisters. The low frequency of X chromosome aberration may be responsible for the lack of somatic abnormalities and the long life in both sisters. The association of pentasomy X mosaicism and diabetes mellitus however appears to be coincidental.

Aneuploidy↗