Proceedings of the National Academy of Sciences of the United States of America, Nov 1, 1985
We report the complete 5025-base sequence of the human 28S rRNA gene. Variability within the spec... more We report the complete 5025-base sequence of the human 28S rRNA gene. Variability within the species has been demonstrated by sequencing a variable region from six separately cloned genes. This region is one of three large subunit rRNA regions that show extreme sequence and size variation among species. The interspecies differences suggest species-specific functions for these sections, while the intraspecies heterogeneity indicates differences among ribosomes. Comparison of the human gene with a partial sequence from the chimpanzee 28S gene yields divergence rates for the two species: 0.8% for conserved regions of the gene and 3.7% for a variable region. The rapid divergence rates of variable regions in the ribosomal gene may permit answers to the question of time of separation of closely related species.
In order to determine whether the regional localizations of Bkm repeats detected on the human X c... more In order to determine whether the regional localizations of Bkm repeats detected on the human X chromosome consisted of typical GATA/GACA repeats, clones were isolated, mapped, and sequenced. Nine Bkm-hybridizing clones from Kunkel's fluorescent-activated, cell-sorted X-chromosome library were all unique. Five were mapped in detail with restriction enzymes and the Bkm-hybridizing segments were localized. Confirmation of X chromosomal homology was obtained for 2 of the clones and Bkm segments from these 2 clones were sequenced. Seventeen contiguous GATA repeats were found in each clone and the overall repeat arrangement showed relatively few differences from previously sequenced Bkm sequences. These are the first sequences of human Bkm repeats. The results, when compared with previously published results, suggest that there may be significant differences between the organization of Bkm repeats on the human X and on the human Y chromosome.
Although advances in the development of positional cloning techniques have rapidly accelerated th... more Although advances in the development of positional cloning techniques have rapidly accelerated the pace of physical mapping and gene localization, the complete and efficient isolation of transcribed sequences from within large targeted genomic regions remains a significant challenge. Here, we describe two approaches used to isolate transcripts encoded within region Xp11.21. First, subcloned genomic fragments derived from regional YAC clones were used to identify evolutionarily conserved sequences (ECSs); ECSs were used to screen cDNA libraries and isolate regional transcripts. Second, YAC DNA was immobilized on a membrane and hybridized to PCR-amplified cDNA clone inserts; selectively retained inserts were subcloned to construct an enriched region-specific cDNA library. Both techniques were successfully used to isolate region-specific transcribed sequences. The advantages and limitations of each approach are discussed.
Geert Mortier Department of Medical Genetics Antwerp University Hospital Prins Boudewijnlaan 43 B... more Geert Mortier Department of Medical Genetics Antwerp University Hospital Prins Boudewijnlaan 43 B–2650 Antwerp (Belgium) Tel. +32 3 275 9773 (secretary) Tel. +32 3 275 9766 (direct) Fax +32 3 275 9723 E-mail: [email protected] Maximilian Muenke Medical Genetics Branch National Human Genome Research Institute National Institutes of Health 35 Convent Drive, MSC 3717 Building 35, Room 1B-203 Bethesda, MD 20892-3717 (USA) Tel. +1 301 402 8167; Fax +1 301 480 7876 E-mail: [email protected]
Proceedings of the National Academy of Sciences, 1985
We report the complete 5025-base sequence of the human 28S rRNA gene. Variability within the spec... more We report the complete 5025-base sequence of the human 28S rRNA gene. Variability within the species has been demonstrated by sequencing a variable region from six separately cloned genes. This region is one of three large subunit rRNA regions that show extreme sequence and size variation among species. The interspecies differences suggest species-specific functions for these sections, while the intraspecies heterogeneity indicates differences among ribosomes. Comparison of the human gene with a partial sequence from the chimpanzee 28S gene yields divergence rates for the two species: 0.8% for conserved regions of the gene and 3.7% for a variable region. The rapid divergence rates of variable regions in the ribosomal gene may permit answers to the question of time of separation of closely related species.
A 3-year-old boy was diagnosed with CHARGE association on the basis of bilat-eral choanal atresia... more A 3-year-old boy was diagnosed with CHARGE association on the basis of bilat-eral choanal atresia, absence of the semicir-cular canals, hypoplastic cochleae, genital hypoplasia, growth and developmental delays, cranial nerve dysfunction, and facial anomalies. Ophthalmologic and cardiac eva-luations were normal. He was found to have an apparently balanced t(2;7)(p14;q21.11) chromosomal translocation. Parental kar-yotypes were normal. Although there is evi-dencesuggesting a geneticbasis forCHARGE association, individuals with chromosomal abnormalities and CHARGE are rare. In the described patient, the presence of charac-teristic CHARGE features suggests that the t(2;7)(p14;q21.11) translocation breakpoints may cause a deletion or disruption of genes within the involved regions that are involved in the generation of the CHARGE association phenotype. # 2001 Wiley-Liss, Inc. KEY WORDS: CHARGE; chromosome; choanal atresia; semicir-cular canals; cochleae; deafness
Complex congenital heart defects (CHD) are associated with a variety of single gene abnormalities... more Complex congenital heart defects (CHD) are associated with a variety of single gene abnormalities and chromosomal rearrangements. Of the various forms of CHD, aortic arch interruption, a conotruncal heart defect, is relatively uncommon. Here we report a male neonate with aortic arch interruption type B, secundum atrial septal defect, perimembranous ventricular septal defect, patent ductus arteriosus, aortic and subaortic stenosis, and trisomy 5q31.1q35.1 resulting from a maternal balanced insertion (20;5). Chromosomal deletions, including deletion 22q11, have been reported with interrupted aortic arch (IAA); however, to our knowledge this is the first report of a trisomy of distal chromosome 5q associated with aortic arch interruption. Here we compare this child’s features to other cases of trisomy 5q31.1q35.1, and review other causes of IAA. We conclude that gene dosage in this chromosomal region likely influences aortic arch development. 2003 Wiley-Liss, Inc.
Purpose Several clinical phenotypes including fetal hydrops, central conducting lymphatic anomaly... more Purpose Several clinical phenotypes including fetal hydrops, central conducting lymphatic anomaly or capillary malformations with arteriovenous malformations 2 (CM-AVM2) have been associated with EPHB4 (Ephrin type B receptor 4) variants, demanding new approaches for deciphering pathogenesis of novel variants of uncertain significance (VUS) identified in EPHB4, and for the identification of differentiated disease mechanisms at the molecular level. Methods Ten index cases with various phenotypes, either fetal hydrops, CM-AVM2, or peripheral lower limb lymphedema, whose distinct clinical phenotypes are described in detail in this study, presented with a variant in EPHB4. In vitro functional studies were performed to confirm pathogenicity. Results Pathogenicity was demonstrated for six of the seven novel EPHB4 VUS investigated. A heterogeneity of molecular disease mechanisms was identified, from loss of protein production or aberrant subcellular localization to total reduction of the p...
American journal of medical genetics. Part A, Jan 19, 2016
Here, we report strong evidence for a role of the FNDC3B gene in craniofacial development. Chromo... more Here, we report strong evidence for a role of the FNDC3B gene in craniofacial development. Chromosomal microarray identified deletions at 3q26.31 in two patients with dysmorphic facial features. Parental FISH studies demonstrated that they are de novo; therefore, these two 3q26.31 microdeletions likely contribute to the patients' dysmorphic features. Interestingly, the minimal region of overlap contains only the FNDC3B gene. Ffibronectin domain III-containing protein 3B (FNDC3B), also known as factor for adipocyte differentiation-104 (FAD104), was first identified as a positive regulator of adipogenesis in a mouse model. Excitingly, further studies in a mouse model have recently demonstrated that FNDC3B is required for normal calvarial bone formation and negatively regulated calvarial cell differentiation through inhibition of BMP/Smad signaling. fndc3b-deficient mice have multiple cranial and skeletal malformations, such as craniosynostosis-like premature calvarial ossification...
Incontinentia pigmenti (IP) is an X-linked dominant disorder characterized by developmental anoma... more Incontinentia pigmenti (IP) is an X-linked dominant disorder characterized by developmental anomalies of the tissues and organs derived from embryonic ectoderm and neuroectoderm. An IP locus, designated IP1, probably resides in Xp11.21, since five unrelated patients with nonfamilial IP have been identified who possess constitutional de novo reciprocal X;autosome translocations involving Xp11.21. We have used a series of somatic cell hybrids containing the rearranged chromosomes derived from three of the five IP1 patients, along with other hybrid cell lines, to map probes in the vicinity of the IP1 locus. Five anonymous DNA loci--DXS422, DXS14, DXS343, DXS429, and DXS370--have been mapped to a region within Xp11.21, between two IP1 X-chromosomal translocation breakpoints; the IP1 t(X;17) breakpoint is proximal (centromeric) to this region, and the IP1 t(X;13) and t(X;9) X-chromosomal breakpoints lie distal to it. While no IP1 translocation breakpoint has yet been identified by pulsed...
Aarskog-Scott syndrome, or Faciogenital dysplasia (FGDY, MIM 305400), is an uncommon X-linked rec... more Aarskog-Scott syndrome, or Faciogenital dysplasia (FGDY, MIM 305400), is an uncommon X-linked recessive developmental disorder that primarily affects skeletal morphogenesis. The condition was first described by Aarskog and Scott in the early 1970s. Mutations in FGD1, the gene responsible for Aarskog-Scott syndrome, result in a developmental disorder affecting specific skeletal structures that include elements of the face, cervical vertebrae, and distal extremities. Genetic and biochemical analyses show that FGD1 encodes a guanine nucleotide exchange factor (GEF), or activator, for Cdc42, a member of the Rho family of Raslike GTPases. Rho proteins comprise a family of at least eight distinct proteins that are involved in the control of a wide variety of cellular functions, including the organization of the actin cytoskeleton, the control of cellular division, and the transcriptional regulation of gene expression. Together, members of the Rho protein family and their activators regulate cell shape, adhesion, and migration, properties that are involved in tissue morphogenesis. The identification that FGD1, the gene responsible for Aarskog-Scott syndrome, is a RhoGEF and a component of the Rho signal transduction pathway suggests that other components of this signaling pathway will be found to be responsible for defects in mammalian morphogenesis.
Congenital adrenal hypoplasia with gonadotropin deficiency is a rare X-linked recessive disorder ... more Congenital adrenal hypoplasia with gonadotropin deficiency is a rare X-linked recessive disorder that usually manifests with symptoms of adrenal insuficiency early in infancy. Adequate replacement therapy with glucocorticoids, mineralocorticoids, and salt has resulted in an increased survival. Slow growth and failure to undergo sexual maturation during the adolescent years usually ensues, secondary to hypogonadotropic hypogonadism. The X-linked congenital adrenal hypoplasia locus has been mapped to region Xp21.3-~21.2. Interstitial deletions of the X chromosome overlapping this region have been observed to cause complex clinical problems, with adrenal hypoplasia as a prominent component. Within a family segregating the disease, there is a 50% risk of having an affected male and a 50% risk of having a carrier female; considerations of genetic heterogeneity, possible chromosomal abnormalities, and prenatal diagnostic studies warrant medical genetic evaluations. The following case presentations illustrate the clinical spectrum of this condition.
To determine the mode of inheritance of familial nonsyndromic Mondini dysplasia. Study Deeign: Co... more To determine the mode of inheritance of familial nonsyndromic Mondini dysplasia. Study Deeign: Correlative clinical genetic analysis of a single kindred. Methods: Clinical history, physical examination, audiologic analysis, computed tomography of the temporal bones, and cytogenetic analysis. Results: The male proband, three affected sisters, and an affected brother are offspring of unaffected parents. The mother and an unaffected brother have audiologic findings suggestive of heterozygous carrier status for a recessive hearing loss gene. Conclusions: Pedigree analysis indicates autosomal recessive inheritance in this family. The observed inheritance and clinical, audiologic, and radiologic findings are different from those previously described for another family with nonsyndromic Mondini dysplasia.' The phenotype in this study family therefore represents a distinct subtype, indicating clinical and genetic heterogeneity of this disorder. This information should facilitate future molecular linkage analyses and genetic counselling of patients with inner ear malformations.
Positional cloning relies on closely spaced regional DNA markers. Here, we report on the combined... more Positional cloning relies on closely spaced regional DNA markers. Here, we report on the combined use of preparative pulsed-field gel electrophoresis (PFGE) and interspersed repetitive sequence (IRS) polymerase chain reaction (PCR) amplification to isolate two DNA markers from a 660 kb SfI fragment that contains locus DXS14 and maps to a region between disease-specific incontinentia pigmenti type 1 (IP1) chromosome translocation breakpoints (1). Genomic DNA from a somatic cell hybrid containing a human X chromosome (GM06318) and a radiation hybrid (RH 128) containing approximately 10% of a human X chromosome, including DNA markers spanning the IP1 X-chromosomal translocation breakpoints within Xpll.21 (2), was digested with
Faciogenital dysplasia (FGDY, MIM*305400), or Aarskog syndrome, is a rare X-linked recessive mult... more Faciogenital dysplasia (FGDY, MIM*305400), or Aarskog syndrome, is a rare X-linked recessive multisystemic disease of abnormal human embryonic development. The disease phenotype consists of a number of facial, skeletal, and urogenital malformations. Major manifestations include disproportionate short stature and shortened distal extremities (Porteous and Goudie 1991). Radiographic abnormalities include hypoplastic phalanges, retarded bone maturation, and a variety of vertebral anomalies including cervical spina bifida occulta, odontoid hypoplasia, and segmentation anomalies. Facial features typically consist of hypertelorism, external ear anomalies, and maxillary hypoplasia. Scrotal anomalies, penile hypospadius, and kidney hypoplasia comprise some of the observed urogenital malformations (Gorlin et al. 1990). Pedigree analyses of families segregating FGDY, and genetic linkage studies in some affected families, confirmed that FGDY was X-linked and mapped to the pericentric region of the human X Chromosome (Chr) (Porteous et al. 1992; Stevenson et al. 1994). FGDY was also mapped to this region on the basis of the observation of a mother and son who both displayed all of the major characteristics of FGDY in association with a reciprocal X;8 chromosome translocation (Bawle et al. 1984). This FGDY-specific translocation breakpoint was mapped by somatic cell and radiation hybrid analyses to a 350-kb interval within Xpll.21 that was flanked by markers ALAS2 and DXS323 (Gorski et al. 1992; Glover et al. 1993). By using a positional cloning strategy, the gene responsible for FGDY, termed FGD1, was recently isolated and characterized (Pasteris et al. 1994). In this study, the mouse FGD1 homolog, Fgdl, was isolated and mapped to the mouse X Chr. A human FGD1 cDNA, clone pFCF3.85 (Pasteris et al. 1994), which contained the entire open reading frame (ORF), was used as a hybridization probe to screen a lambda gtl0 library derived from e7.5 mouse embryonic ectoderm. The three mouse cDNA clones with the largest inserts were subcloned into Bluescript KSII(+) and sequenced (Pasteris et al. 1994). To facilitate DNA sequencing, we used oligonucleotides directed against the human FGD1 sequence for sequencing; directed against the mouse cDNAs, 80% of these oligonucleotide primers yielded interpretable sequence data. These results sug-The nucleotide sequence data reported in this paper have been submitted to GenBank and have been assigned the accession number U22325.
Proceedings of the National Academy of Sciences of the United States of America, Nov 1, 1985
We report the complete 5025-base sequence of the human 28S rRNA gene. Variability within the spec... more We report the complete 5025-base sequence of the human 28S rRNA gene. Variability within the species has been demonstrated by sequencing a variable region from six separately cloned genes. This region is one of three large subunit rRNA regions that show extreme sequence and size variation among species. The interspecies differences suggest species-specific functions for these sections, while the intraspecies heterogeneity indicates differences among ribosomes. Comparison of the human gene with a partial sequence from the chimpanzee 28S gene yields divergence rates for the two species: 0.8% for conserved regions of the gene and 3.7% for a variable region. The rapid divergence rates of variable regions in the ribosomal gene may permit answers to the question of time of separation of closely related species.
In order to determine whether the regional localizations of Bkm repeats detected on the human X c... more In order to determine whether the regional localizations of Bkm repeats detected on the human X chromosome consisted of typical GATA/GACA repeats, clones were isolated, mapped, and sequenced. Nine Bkm-hybridizing clones from Kunkel's fluorescent-activated, cell-sorted X-chromosome library were all unique. Five were mapped in detail with restriction enzymes and the Bkm-hybridizing segments were localized. Confirmation of X chromosomal homology was obtained for 2 of the clones and Bkm segments from these 2 clones were sequenced. Seventeen contiguous GATA repeats were found in each clone and the overall repeat arrangement showed relatively few differences from previously sequenced Bkm sequences. These are the first sequences of human Bkm repeats. The results, when compared with previously published results, suggest that there may be significant differences between the organization of Bkm repeats on the human X and on the human Y chromosome.
Although advances in the development of positional cloning techniques have rapidly accelerated th... more Although advances in the development of positional cloning techniques have rapidly accelerated the pace of physical mapping and gene localization, the complete and efficient isolation of transcribed sequences from within large targeted genomic regions remains a significant challenge. Here, we describe two approaches used to isolate transcripts encoded within region Xp11.21. First, subcloned genomic fragments derived from regional YAC clones were used to identify evolutionarily conserved sequences (ECSs); ECSs were used to screen cDNA libraries and isolate regional transcripts. Second, YAC DNA was immobilized on a membrane and hybridized to PCR-amplified cDNA clone inserts; selectively retained inserts were subcloned to construct an enriched region-specific cDNA library. Both techniques were successfully used to isolate region-specific transcribed sequences. The advantages and limitations of each approach are discussed.
Geert Mortier Department of Medical Genetics Antwerp University Hospital Prins Boudewijnlaan 43 B... more Geert Mortier Department of Medical Genetics Antwerp University Hospital Prins Boudewijnlaan 43 B–2650 Antwerp (Belgium) Tel. +32 3 275 9773 (secretary) Tel. +32 3 275 9766 (direct) Fax +32 3 275 9723 E-mail: [email protected] Maximilian Muenke Medical Genetics Branch National Human Genome Research Institute National Institutes of Health 35 Convent Drive, MSC 3717 Building 35, Room 1B-203 Bethesda, MD 20892-3717 (USA) Tel. +1 301 402 8167; Fax +1 301 480 7876 E-mail: [email protected]
Proceedings of the National Academy of Sciences, 1985
We report the complete 5025-base sequence of the human 28S rRNA gene. Variability within the spec... more We report the complete 5025-base sequence of the human 28S rRNA gene. Variability within the species has been demonstrated by sequencing a variable region from six separately cloned genes. This region is one of three large subunit rRNA regions that show extreme sequence and size variation among species. The interspecies differences suggest species-specific functions for these sections, while the intraspecies heterogeneity indicates differences among ribosomes. Comparison of the human gene with a partial sequence from the chimpanzee 28S gene yields divergence rates for the two species: 0.8% for conserved regions of the gene and 3.7% for a variable region. The rapid divergence rates of variable regions in the ribosomal gene may permit answers to the question of time of separation of closely related species.
A 3-year-old boy was diagnosed with CHARGE association on the basis of bilat-eral choanal atresia... more A 3-year-old boy was diagnosed with CHARGE association on the basis of bilat-eral choanal atresia, absence of the semicir-cular canals, hypoplastic cochleae, genital hypoplasia, growth and developmental delays, cranial nerve dysfunction, and facial anomalies. Ophthalmologic and cardiac eva-luations were normal. He was found to have an apparently balanced t(2;7)(p14;q21.11) chromosomal translocation. Parental kar-yotypes were normal. Although there is evi-dencesuggesting a geneticbasis forCHARGE association, individuals with chromosomal abnormalities and CHARGE are rare. In the described patient, the presence of charac-teristic CHARGE features suggests that the t(2;7)(p14;q21.11) translocation breakpoints may cause a deletion or disruption of genes within the involved regions that are involved in the generation of the CHARGE association phenotype. # 2001 Wiley-Liss, Inc. KEY WORDS: CHARGE; chromosome; choanal atresia; semicir-cular canals; cochleae; deafness
Complex congenital heart defects (CHD) are associated with a variety of single gene abnormalities... more Complex congenital heart defects (CHD) are associated with a variety of single gene abnormalities and chromosomal rearrangements. Of the various forms of CHD, aortic arch interruption, a conotruncal heart defect, is relatively uncommon. Here we report a male neonate with aortic arch interruption type B, secundum atrial septal defect, perimembranous ventricular septal defect, patent ductus arteriosus, aortic and subaortic stenosis, and trisomy 5q31.1q35.1 resulting from a maternal balanced insertion (20;5). Chromosomal deletions, including deletion 22q11, have been reported with interrupted aortic arch (IAA); however, to our knowledge this is the first report of a trisomy of distal chromosome 5q associated with aortic arch interruption. Here we compare this child’s features to other cases of trisomy 5q31.1q35.1, and review other causes of IAA. We conclude that gene dosage in this chromosomal region likely influences aortic arch development. 2003 Wiley-Liss, Inc.
Purpose Several clinical phenotypes including fetal hydrops, central conducting lymphatic anomaly... more Purpose Several clinical phenotypes including fetal hydrops, central conducting lymphatic anomaly or capillary malformations with arteriovenous malformations 2 (CM-AVM2) have been associated with EPHB4 (Ephrin type B receptor 4) variants, demanding new approaches for deciphering pathogenesis of novel variants of uncertain significance (VUS) identified in EPHB4, and for the identification of differentiated disease mechanisms at the molecular level. Methods Ten index cases with various phenotypes, either fetal hydrops, CM-AVM2, or peripheral lower limb lymphedema, whose distinct clinical phenotypes are described in detail in this study, presented with a variant in EPHB4. In vitro functional studies were performed to confirm pathogenicity. Results Pathogenicity was demonstrated for six of the seven novel EPHB4 VUS investigated. A heterogeneity of molecular disease mechanisms was identified, from loss of protein production or aberrant subcellular localization to total reduction of the p...
American journal of medical genetics. Part A, Jan 19, 2016
Here, we report strong evidence for a role of the FNDC3B gene in craniofacial development. Chromo... more Here, we report strong evidence for a role of the FNDC3B gene in craniofacial development. Chromosomal microarray identified deletions at 3q26.31 in two patients with dysmorphic facial features. Parental FISH studies demonstrated that they are de novo; therefore, these two 3q26.31 microdeletions likely contribute to the patients' dysmorphic features. Interestingly, the minimal region of overlap contains only the FNDC3B gene. Ffibronectin domain III-containing protein 3B (FNDC3B), also known as factor for adipocyte differentiation-104 (FAD104), was first identified as a positive regulator of adipogenesis in a mouse model. Excitingly, further studies in a mouse model have recently demonstrated that FNDC3B is required for normal calvarial bone formation and negatively regulated calvarial cell differentiation through inhibition of BMP/Smad signaling. fndc3b-deficient mice have multiple cranial and skeletal malformations, such as craniosynostosis-like premature calvarial ossification...
Incontinentia pigmenti (IP) is an X-linked dominant disorder characterized by developmental anoma... more Incontinentia pigmenti (IP) is an X-linked dominant disorder characterized by developmental anomalies of the tissues and organs derived from embryonic ectoderm and neuroectoderm. An IP locus, designated IP1, probably resides in Xp11.21, since five unrelated patients with nonfamilial IP have been identified who possess constitutional de novo reciprocal X;autosome translocations involving Xp11.21. We have used a series of somatic cell hybrids containing the rearranged chromosomes derived from three of the five IP1 patients, along with other hybrid cell lines, to map probes in the vicinity of the IP1 locus. Five anonymous DNA loci--DXS422, DXS14, DXS343, DXS429, and DXS370--have been mapped to a region within Xp11.21, between two IP1 X-chromosomal translocation breakpoints; the IP1 t(X;17) breakpoint is proximal (centromeric) to this region, and the IP1 t(X;13) and t(X;9) X-chromosomal breakpoints lie distal to it. While no IP1 translocation breakpoint has yet been identified by pulsed...
Aarskog-Scott syndrome, or Faciogenital dysplasia (FGDY, MIM 305400), is an uncommon X-linked rec... more Aarskog-Scott syndrome, or Faciogenital dysplasia (FGDY, MIM 305400), is an uncommon X-linked recessive developmental disorder that primarily affects skeletal morphogenesis. The condition was first described by Aarskog and Scott in the early 1970s. Mutations in FGD1, the gene responsible for Aarskog-Scott syndrome, result in a developmental disorder affecting specific skeletal structures that include elements of the face, cervical vertebrae, and distal extremities. Genetic and biochemical analyses show that FGD1 encodes a guanine nucleotide exchange factor (GEF), or activator, for Cdc42, a member of the Rho family of Raslike GTPases. Rho proteins comprise a family of at least eight distinct proteins that are involved in the control of a wide variety of cellular functions, including the organization of the actin cytoskeleton, the control of cellular division, and the transcriptional regulation of gene expression. Together, members of the Rho protein family and their activators regulate cell shape, adhesion, and migration, properties that are involved in tissue morphogenesis. The identification that FGD1, the gene responsible for Aarskog-Scott syndrome, is a RhoGEF and a component of the Rho signal transduction pathway suggests that other components of this signaling pathway will be found to be responsible for defects in mammalian morphogenesis.
Congenital adrenal hypoplasia with gonadotropin deficiency is a rare X-linked recessive disorder ... more Congenital adrenal hypoplasia with gonadotropin deficiency is a rare X-linked recessive disorder that usually manifests with symptoms of adrenal insuficiency early in infancy. Adequate replacement therapy with glucocorticoids, mineralocorticoids, and salt has resulted in an increased survival. Slow growth and failure to undergo sexual maturation during the adolescent years usually ensues, secondary to hypogonadotropic hypogonadism. The X-linked congenital adrenal hypoplasia locus has been mapped to region Xp21.3-~21.2. Interstitial deletions of the X chromosome overlapping this region have been observed to cause complex clinical problems, with adrenal hypoplasia as a prominent component. Within a family segregating the disease, there is a 50% risk of having an affected male and a 50% risk of having a carrier female; considerations of genetic heterogeneity, possible chromosomal abnormalities, and prenatal diagnostic studies warrant medical genetic evaluations. The following case presentations illustrate the clinical spectrum of this condition.
To determine the mode of inheritance of familial nonsyndromic Mondini dysplasia. Study Deeign: Co... more To determine the mode of inheritance of familial nonsyndromic Mondini dysplasia. Study Deeign: Correlative clinical genetic analysis of a single kindred. Methods: Clinical history, physical examination, audiologic analysis, computed tomography of the temporal bones, and cytogenetic analysis. Results: The male proband, three affected sisters, and an affected brother are offspring of unaffected parents. The mother and an unaffected brother have audiologic findings suggestive of heterozygous carrier status for a recessive hearing loss gene. Conclusions: Pedigree analysis indicates autosomal recessive inheritance in this family. The observed inheritance and clinical, audiologic, and radiologic findings are different from those previously described for another family with nonsyndromic Mondini dysplasia.' The phenotype in this study family therefore represents a distinct subtype, indicating clinical and genetic heterogeneity of this disorder. This information should facilitate future molecular linkage analyses and genetic counselling of patients with inner ear malformations.
Positional cloning relies on closely spaced regional DNA markers. Here, we report on the combined... more Positional cloning relies on closely spaced regional DNA markers. Here, we report on the combined use of preparative pulsed-field gel electrophoresis (PFGE) and interspersed repetitive sequence (IRS) polymerase chain reaction (PCR) amplification to isolate two DNA markers from a 660 kb SfI fragment that contains locus DXS14 and maps to a region between disease-specific incontinentia pigmenti type 1 (IP1) chromosome translocation breakpoints (1). Genomic DNA from a somatic cell hybrid containing a human X chromosome (GM06318) and a radiation hybrid (RH 128) containing approximately 10% of a human X chromosome, including DNA markers spanning the IP1 X-chromosomal translocation breakpoints within Xpll.21 (2), was digested with
Faciogenital dysplasia (FGDY, MIM*305400), or Aarskog syndrome, is a rare X-linked recessive mult... more Faciogenital dysplasia (FGDY, MIM*305400), or Aarskog syndrome, is a rare X-linked recessive multisystemic disease of abnormal human embryonic development. The disease phenotype consists of a number of facial, skeletal, and urogenital malformations. Major manifestations include disproportionate short stature and shortened distal extremities (Porteous and Goudie 1991). Radiographic abnormalities include hypoplastic phalanges, retarded bone maturation, and a variety of vertebral anomalies including cervical spina bifida occulta, odontoid hypoplasia, and segmentation anomalies. Facial features typically consist of hypertelorism, external ear anomalies, and maxillary hypoplasia. Scrotal anomalies, penile hypospadius, and kidney hypoplasia comprise some of the observed urogenital malformations (Gorlin et al. 1990). Pedigree analyses of families segregating FGDY, and genetic linkage studies in some affected families, confirmed that FGDY was X-linked and mapped to the pericentric region of the human X Chromosome (Chr) (Porteous et al. 1992; Stevenson et al. 1994). FGDY was also mapped to this region on the basis of the observation of a mother and son who both displayed all of the major characteristics of FGDY in association with a reciprocal X;8 chromosome translocation (Bawle et al. 1984). This FGDY-specific translocation breakpoint was mapped by somatic cell and radiation hybrid analyses to a 350-kb interval within Xpll.21 that was flanked by markers ALAS2 and DXS323 (Gorski et al. 1992; Glover et al. 1993). By using a positional cloning strategy, the gene responsible for FGDY, termed FGD1, was recently isolated and characterized (Pasteris et al. 1994). In this study, the mouse FGD1 homolog, Fgdl, was isolated and mapped to the mouse X Chr. A human FGD1 cDNA, clone pFCF3.85 (Pasteris et al. 1994), which contained the entire open reading frame (ORF), was used as a hybridization probe to screen a lambda gtl0 library derived from e7.5 mouse embryonic ectoderm. The three mouse cDNA clones with the largest inserts were subcloned into Bluescript KSII(+) and sequenced (Pasteris et al. 1994). To facilitate DNA sequencing, we used oligonucleotides directed against the human FGD1 sequence for sequencing; directed against the mouse cDNAs, 80% of these oligonucleotide primers yielded interpretable sequence data. These results sug-The nucleotide sequence data reported in this paper have been submitted to GenBank and have been assigned the accession number U22325.
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Papers by Jerome Gorski