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1.
Am J Hum Genet ; 105(4): 836-843, 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31564437

RESUMO

Osteogenesis imperfecta (OI) comprises a genetically heterogeneous group of skeletal fragility diseases. Here, we report on five independent families with a progressively deforming type of OI, in whom we identified four homozygous truncation or frameshift mutations in MESD. Affected individuals had recurrent fractures and at least one had oligodontia. MESD encodes an endoplasmic reticulum (ER) chaperone protein for the canonical Wingless-related integration site (WNT) signaling receptors LRP5 and LRP6. Because complete absence of MESD causes embryonic lethality in mice, we hypothesized that the OI-associated mutations are hypomorphic alleles since these mutations occur downstream of the chaperone activity domain but upstream of ER-retention domain. This would be consistent with the clinical phenotypes of skeletal fragility and oligodontia in persons deficient for LRP5 and LRP6, respectively. When we expressed wild-type (WT) and mutant MESD in HEK293T cells, we detected WT MESD in cell lysate but not in conditioned medium, whereas the converse was true for mutant MESD. We observed that both WT and mutant MESD retained the ability to chaperone LRP5. Thus, OI-associated MESD mutations produce hypomorphic alleles whose failure to remain within the ER significantly reduces but does not completely eliminate LRP5 and LRP6 trafficking. Since these individuals have no eye abnormalities (which occur in individuals completely lacking LRP5) and have neither limb nor brain patterning defects (both of which occur in mice completely lacking LRP6), we infer that bone mass accrual and dental patterning are more sensitive to reduced canonical WNT signaling than are other developmental processes. Biologic agents that can increase LRP5 and LRP6-mediated WNT signaling could benefit individuals with MESD-associated OI.

2.
Orphanet J Rare Dis ; 14(1): 219, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31533771

RESUMO

BACKGROUND: Osteogenesis imperfecta (OI) is a rare disease leading to hereditary bone fragility. Nearly 90% of cases are caused by mutations in the collagen genes COL1A1/A2 (classical OI) leading to multiple fractures, scoliosis, short stature and nonskeletal findings as blue sclera, hypermobility of joints, bone pain and delayed motor function development. Bisphosphonates are used in most moderate and severely affected patients assuming that an increase of bone mineral density might reduce fractures and bone pain in patients with OI. Denosumab as a RANK ligand antibody inhibiting osteoclast maturation has been approved for osteoporosis treatment in adults. First data from small clinical trials promised a high efficacy of Denosumab in children with OI. Aim of this analysis was a retrospective evaluation of an individualized biomarker-associated treatment regime with Denosumab in 10 children with classical OI which were followed for 1 year after their participation in a pilot trial with Denosumab. Therefore urinary deoxypyridinoline levels were evaluated frequently as an osteoclastic activity marker and depending on that levels Denosumab injections were scheduled individually. METHODS: Ten patients (age range: 6.16-12.13 years; all participated in the former OI-AK phase 2 trial (NCT01799798)) were included in the follow-up period. Denosumab was administered subcutaneously depending on the individual urinary excretion course of deoxypyridinoline (DPD/Crea) as osteoclastic activity marker with 1 mg/kg body weight. DPD/Crea levels were evaluated before denosumab administration and afterwards. If patients present after an initial decrease after injection with a re-increase up to the DPD/crea level before Denosumab injection next dosage was planned. Changes of areal bone mineral density (aBMD) using dual energy x-ray absorptiometry of the lumbar spine after 12 month was evaluated. Safety was assessed by bone metabolism markers and side effect reporting. RESULTS: During follow-up mean relative change of lumbar aBMD was - 6.4%. Lumbar spine aBMD z-Scores decreased from - 1.01 ± 2.61 (mean ± SD) to - 1.91 ± 2.12 (p = 0.015). Mobility changed not significantly (GMFM-88 -6.49 ± 8.85% (p = 0.08). No severe side effects occurred. Dose intervals could be extended in the mean from 12 weeks previously to 20.3 weeks. CONCLUSIONS: On average, it was possible to prolong the intervals between drug administrations and to reduce the total dose about by 25% without a decrease of mobility or change of vertebral shape despite a reduction of lumbar aBMD during 1 year of biomarker-directed Denosumab treatment. Further trials are necessary to balance side effects and highest efficacy in children.

3.
Am J Hum Genet ; 104(4): 749-757, 2019 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-30905398

RESUMO

Over a relatively short period of time, the clinical geneticist's "toolbox" has been expanded by machine-learning algorithms for image analysis, which can be applied to the task of syndrome identification on the basis of facial photographs, but these technologies harbor potential beyond the recognition of established phenotypes. Here, we comprehensively characterized two individuals with a hitherto unknown genetic disorder caused by the same de novo mutation in LEMD2 (c.1436C>T;p.Ser479Phe), the gene which encodes the nuclear envelope protein LEM domain-containing protein 2 (LEMD2). Despite different ages and ethnic backgrounds, both individuals share a progeria-like facial phenotype and a distinct combination of physical and neurologic anomalies, such as growth retardation; hypoplastic jaws crowded with multiple supernumerary, yet unerupted, teeth; and cerebellar intention tremor. Immunofluorescence analyses of patient fibroblasts revealed mutation-induced disturbance of nuclear architecture, recapitulating previously published data in LEMD2-deficient cell lines, and additional experiments suggested mislocalization of mutant LEMD2 protein within the nuclear lamina. Computational analysis of facial features with two different deep neural networks showed phenotypic proximity to other nuclear envelopathies. One of the algorithms, when trained to recognize syndromic similarity (rather than specific syndromes) in an unsupervised approach, clustered both individuals closely together, providing hypothesis-free hints for a common genetic etiology. We show that a recurrent de novo mutation in LEMD2 causes a nuclear envelopathy whose prognosis in adolescence is relatively good in comparison to that of classical Hutchinson-Gilford progeria syndrome, and we suggest that the application of artificial intelligence to the analysis of patient images can facilitate the discovery of new genetic disorders.

4.
Mol Cell Probes ; 45: 84-88, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30914295

RESUMO

When deciding on which genes to assess in larger Next-Generation Sequencing (NGS) datasets for the molecular genetic diagnosis of intellectual disability (ID), geneticists today have a variety of gene-phenotype databases and expert-curated gene lists available. To quantify their respective completeness, we compare an ID gene selection auto-generated from the Human Phenotype Ontology gene-phenotype association database and expert-curated ID gene lists from three reputable sources (sysID, the DDD consortium and Genomics England) and analyse some of their differences. We give examples of what we regard as genuine gaps ("missing ID genes") for each of these and conclude that a complementary or consensus approach is needed to maximise diagnostic yield in ID patients. We propose several consensus gene lists with ID-associated genes of different confidence levels.

5.
Eur J Hum Genet ; 26(9): 1392-1395, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29891879

RESUMO

Complete uniparental isodisomy (iUPD)-the presence of two identical chromosomes in an individual that originate from only a single parental homolog-is an underestimated cause of recessive Mendelian disease in humans. Correctly identifying iUPD in an index patient is of enormous consequence to correctly counseling the family/couple, as the recurrence risk for siblings is reduced from 25% to usually <1%. In medium/large-scale NGS analyses, we found that complete iUPD can be rapidly and straightforwardly inferred from a singleton dataset (index patient only) through a simple chromosome- and genotype-filtering step in <1 min. We discuss the opportunities of iUPD detection in medium/large-scale NGS analyses by example of a case of CHRNG-associated multiple pterygium syndrome due to complete maternal iUPD. Using computer simulations for several detection thresholds, we validate and estimate sensitivity, specificity, positive (PPV), and negative predictive values (NPV) of the proposed screening method for reliable detection of complete iUPD. When screening for complete iUPD, our models suggest that a >85% proportion of homozygous calls on a single chromosome with ≥30 sufficiently interspaced called variants results in a sensitivity of 97.9% and specificity of 99.7%. The PPV is 95.1%, the NPV 99.9%. When this threshold is exceeded for a chromosome on which a patient harbors an apparently homozygous disease-associated variant, it should be sufficient cause to discuss iUPD as a plausible or probable mechanism of disease in the genetic analysis report, even when parental segregation has not (yet) been performed.

6.
J Lipid Res ; 59(8): 1529-1535, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29866657

RESUMO

Copy-number variations (CNVs) have been studied in the context of familial hypercholesterolemia but have not yet been evaluated in patients with extreme levels of HDL cholesterol. We evaluated targeted, next-generation sequencing data from patients with very low levels of HDL cholesterol (i.e., hypoalphalipoproteinemia) with the VarSeq-CNV® caller algorithm to screen for CNVs that disrupted the ABCA1, LCAT, or APOA1 genes. In four individuals, we found three unique deletions in ABCA1: a heterozygous deletion of exon 4, a heterozygous deletion that spanned exons 8 to 31, and a heterozygous deletion of the entire ABCA1 gene. Breakpoints were identified with Sanger sequencing, and the full-gene deletion was confirmed by using exome sequencing and the Affymetrix CytoScan HD array. Previously, large-scale deletions in candidate HDL genes had not been associated with hypoalphalipoproteinemia; our findings indicate that CNVs in ABCA1 may be a previously unappreciated genetic determinant of low levels of HDL cholesterol. By coupling bioinformatic analyses with next-generation sequencing data, we can successfully assess the spectrum of genetic determinants of many dyslipidemias, including hypoalphalipoproteinemia.

7.
Am J Hum Genet ; 101(5): 833-843, 2017 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-29100093

RESUMO

Gorlin-Chaudhry-Moss syndrome (GCMS) is a dysmorphic syndrome characterized by coronal craniosynostosis and severe midface hypoplasia, body and facial hypertrichosis, microphthalmia, short stature, and short distal phalanges. Variable lipoatrophy and cutis laxa are the basis for a progeroid appearance. Using exome and genome sequencing, we identified the recurrent de novo mutations c.650G>A (p.Arg217His) and c.649C>T (p.Arg217Cys) in SLC25A24 in five unrelated girls diagnosed with GCMS. Two of the girls had pronounced neonatal progeroid features and were initially diagnosed with Wiedemann-Rautenstrauch syndrome. SLC25A24 encodes a mitochondrial inner membrane ATP-Mg/Pi carrier. In fibroblasts from affected individuals, the mutated SLC25A24 showed normal stability. In contrast to control cells, the probands' cells showed mitochondrial swelling, which was exacerbated upon treatment with hydrogen peroxide (H2O2). The same effect was observed after overexpression of the mutant cDNA. Under normal culture conditions, the mitochondrial membrane potential of the probands' fibroblasts was intact, whereas ATP content in the mitochondrial matrix was lower than that in control cells. However, upon H2O2 exposure, the membrane potential was significantly elevated in cells harboring the mutated SLC25A24. No reduction of mitochondrial DNA copy number was observed. These findings demonstrate that mitochondrial dysfunction with increased sensitivity to oxidative stress is due to the SLC25A24 mutations. Our results suggest that the SLC25A24 mutations induce a gain of pathological function and link mitochondrial ATP-Mg/Pi transport to the development of skeletal and connective tissue.


Assuntos
Anormalidades Múltiplas/genética , Antiporters/genética , Proteínas de Ligação ao Cálcio/genética , Anormalidades Craniofaciais/genética , Craniossinostoses/genética , Permeabilidade do Canal Arterial/genética , Hipertricose/genética , Mitocôndrias/genética , Proteínas Mitocondriais/genética , Mutação/genética , Trifosfato de Adenosina/genética , Adolescente , Criança , Pré-Escolar , Cútis Laxa/genética , DNA Mitocondrial/genética , Exoma/genética , Feminino , Retardo do Crescimento Fetal/genética , Fibroblastos/patologia , Humanos , Peróxido de Hidrogênio/farmacologia , Lactente , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Potencial da Membrana Mitocondrial/genética , Mitocôndrias/efeitos dos fármacos , Estresse Oxidativo/genética , Progéria/genética
8.
Am J Med Genet A ; 173(8): 2132-2138, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28574232

RESUMO

Recently, a new syndrome with intellectual disability (ID) and dysmorphic features due to deletions or point mutations within the TBL1XR1 gene located in the chromosomal band 3q26.32 has been described (MRD41, OMIM 616944). One recurrent point mutation in the TBL1XR1 gene has been identified as the cause of Pierpont syndrome (OMIM 602342), a distinct intellectual disability syndrome with plantar lipomatosis. In addition, different de novo point mutations in the TBL1XR1 gene have been found in patients with autism spectrum disorders (ASD) and intellectual disability. Here, we report four patients from two unrelated families in whom array-CGH analysis and real-time quantitative PCR of genomic DNA revealed a TBL1XR1-microduplication. Adjacent genes were not affected. The microduplication occurred as a de novo event in one patient, whereas the other three cases occurred in two generations of a second, unrelated family. We compare and contrast the clinical findings in TBL1XR1 microdeletion, point mutation, and microduplication cases and expand the TBL1XR1-associated phenotypic spectrum. ID, hearing loss, and ASD are common features of TBL1XR1-associated diseases. Our clinical observations add to the increasing evidence of the role of TBL1XR1 in brain development, and they simultaneously demonstrate that different genetic disease mechanisms affecting TBL1XR1 can lead to similar ID phenotypes. The TBL1XR1-microduplication syndrome is an intellectual disability/learning disability syndrome with associated incomplete penetrance ASD, hearing loss, and delay of puberty. Its phenotypic overlap indicates that it is a genomic sister-disorder to the 3q26.32 microdeletion syndrome.


Assuntos
Transtorno do Espectro Autista/genética , Perda Auditiva/genética , Deficiência Intelectual/genética , Proteínas Nucleares/genética , Receptores Citoplasmáticos e Nucleares/genética , Proteínas Repressoras/genética , Adolescente , Adulto , Transtorno do Espectro Autista/fisiopatologia , Criança , Cromossomos Humanos Par 3/genética , Hibridização Genômica Comparativa , Feminino , Duplicação Gênica , Genômica , Perda Auditiva/fisiopatologia , Humanos , Deficiência Intelectual/fisiopatologia , Masculino , Maturidade Sexual/genética , Irmãos
10.
Hum Mutat ; 37(9): 847-64, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27302555

RESUMO

Kabuki syndrome (KS) is a rare but recognizable condition that consists of a characteristic face, short stature, various organ malformations, and a variable degree of intellectual disability. Mutations in KMT2D have been identified as the main cause for KS, whereas mutations in KDM6A are a much less frequent cause. Here, we report a mutation screening in a case series of 347 unpublished patients, in which we identified 12 novel KDM6A mutations (KS type 2) and 208 mutations in KMT2D (KS type 1), 132 of them novel. Two of the KDM6A mutations were maternally inherited and nine were shown to be de novo. We give an up-to-date overview of all published mutations for the two KS genes and point out possible mutation hot spots and strategies for molecular genetic testing. We also report the clinical details for 11 patients with KS type 2, summarize the published clinical information, specifically with a focus on the less well-defined X-linked KS type 2, and comment on phenotype-genotype correlations as well as sex-specific phenotypic differences. Finally, we also discuss a possible role of KDM6A in Kabuki-like Turner syndrome and report a mutation screening of KDM6C (UTY) in male KS patients.


Assuntos
Anormalidades Múltiplas/genética , Proteínas de Ligação a DNA/genética , Face/anormalidades , Doenças Hematológicas/genética , Histona Desmetilases/genética , Mutação , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Doenças Vestibulares/genética , Anormalidades Múltiplas/patologia , Face/patologia , Feminino , Genes Ligados ao Cromossomo X , Predisposição Genética para Doença , Doenças Hematológicas/patologia , Humanos , Masculino , Herança Materna , Síndrome de Noonan/genética , Análise de Sequência de DNA , Doenças Vestibulares/patologia
11.
Wien Med Wochenschr ; 165(13-14): 278-84, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26055811

RESUMO

Osteogenesis imperfecta is a rare hereditary disease mostly caused by mutations impairing collagen synthesis and modification. Recently recessive forms have been described influencing differentiation and activity of osteoblasts and osteoclasts. Most prominent signs are fractures due to low traumata and deformities of long bones and vertebrae. Additional patients can be affected by dwarfism, scoliosis Dentinogenesis imperfecta, deafness and a blueish discoloration of the sclera. During childhood state of the art medical treatment are i.v. bisphosphonates to increase bone mass and to reduce fracture rate. Surgical interventions are needed to treat fractures, to correct deformities and should always be accompanied by physiotherapeutic and rehabilitative interventions.


Assuntos
Osteogênese Imperfeita/fisiopatologia , Osteogênese Imperfeita/terapia , Colágeno Tipo I/genética , Terapia Combinada , Análise Mutacional de DNA , Difosfonatos/administração & dosagem , Feminino , Fixação de Fratura , Fraturas Espontâneas/genética , Fraturas Espontâneas/fisiopatologia , Fraturas Espontâneas/terapia , Triagem de Portadores Genéticos , Humanos , Lactente , Recém-Nascido , Infusões Intravenosas , Masculino , Osteoblastos/fisiologia , Osteoclastos/fisiologia , Osteogênese Imperfeita/genética , Modalidades de Fisioterapia
12.
Am J Hum Genet ; 96(3): 432-9, 2015 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-25683121

RESUMO

As a result of a whole-exome sequencing study, we report three mutant alleles in SEC24D, a gene encoding a component of the COPII complex involved in protein export from the ER: the truncating mutation c.613C>T (p.Gln205(∗)) and the missense mutations c.3044C>T (p.Ser1015Phe, located in a cargo-binding pocket) and c.2933A>C (p.Gln978Pro, located in the gelsolin-like domain). Three individuals from two families affected by a similar skeletal phenotype were each compound heterozygous for two of these mutant alleles, with c.3044C>T being embedded in a 14 Mb founder haplotype shared by all three. The affected individuals were a 7-year-old boy with a phenotype most closely resembling Cole-Carpenter syndrome and two fetuses initially suspected to have a severe type of osteogenesis imperfecta. All three displayed a severely disturbed ossification of the skull and multiple fractures with prenatal onset. The 7-year-old boy had short stature and craniofacial malformations including macrocephaly, midface hypoplasia, micrognathia, frontal bossing, and down-slanting palpebral fissures. Electron and immunofluorescence microscopy of skin fibroblasts of this individual revealed that ER export of procollagen was inefficient and that ER tubules were dilated, faithfully reproducing the cellular phenotype of individuals with cranio-lentico-sutural dysplasia (CLSD). CLSD is caused by SEC23A mutations and displays a largely overlapping craniofacial phenotype, but it is not characterized by generalized bone fragility and presented with cataracts in the original family described. The cellular and morphological phenotypes we report are in concordance with the phenotypes described for the Sec24d-deficient fish mutants vbi (medaka) and bulldog (zebrafish).


Assuntos
Craniossinostoses/genética , Anormalidades do Olho/genética , Hidrocefalia/genética , Osteogênese Imperfeita/genética , Proteínas de Transporte Vesicular/genética , Alelos , Animais , Osso e Ossos/patologia , Criança , Retículo Endoplasmático/metabolismo , Feminino , Heterozigoto , Humanos , Masculino , Mutação de Sentido Incorreto , Linhagem , Fenótipo , Conformação Proteica , Análise de Sequência de DNA , Proteínas de Transporte Vesicular/metabolismo , Peixe-Zebra/genética
13.
Orphanet J Rare Dis ; 9: 145, 2014 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-25257953

RESUMO

BACKGROUND: Osteogenesis imperfecta (OI) is a hereditary disease causing reduced bone mass, increased fracture rate, long bone deformities and vertebral compressions. Additional non skeletal findings are caused by impaired collagen function and include hyperlaxity of joints and blue sclera. Most OI cases are caused by dominant mutations in COL1A1/2 affecting bone formation. During the last years, recessive forms of OI have been identified, mostly affecting posttranslational modification of collagen. In 2011, mutations in SERPINF1 were identified as the molecular cause of OI type VI, and thereby a novel pathophysiology of the disease was elucidated. The subgroup of patients with OI type VI are affected by an increased bone resorption, leading to the same symptoms as observed in patients with an impaired bone formation. Severely affected children are currently treated with intravenous bisphosphonates regardless of the underlying mutation and pathophysiology. Patients with OI type VI are known to have a poor response to such a bisphosphonate treatment. METHOD: Deciphering the genetic cause of OI type VI in our 4 patients (three children and one adolescent) led to an immediate translational approach in the form of a treatment with the monoclonal RANKL antibody Denosumab (1 mg/kg body weight every 12 weeks). RESULTS: Short-term biochemical response to this treatment was reported previously. We now present the results after 2 years of treatment and demonstrate a long term benefit as well as an increase of bone mineral density, a normalization of vertebral shape, an increase of mobility, and a reduced fracture rate. CONCLUSION: This report presents the first two-year data of denosumab treatment in patients with Osteogenesis imperfecta type VI and in Osteogenesis imperfecta in general as an effective and apparently safe treatment option.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Osteogênese Imperfeita/diagnóstico por imagem , Osteogênese Imperfeita/tratamento farmacológico , Ligante RANK/antagonistas & inibidores , Anticorpos Monoclonais Humanizados/farmacologia , Densidade Óssea/efeitos dos fármacos , Densidade Óssea/fisiologia , Criança , Denosumab , Feminino , Humanos , Masculino , Radiografia , Fatores de Tempo , Adulto Jovem
14.
J Bone Miner Res ; 29(6): 1387-91, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24293101

RESUMO

Osteogenesis imperfecta (OI) is a hereditary connective tissue disorder characterized by a wide range of skeletal symptoms. Most patients have dominantly inherited or de novo mutations in COL1A1 or COL1A2. Up to 5% of patients have OI type V, characterized by hyperplastic callus formation after fractures, calcification of the interosseous membrane of the forearm, and a mesh-like lamellation pattern observed in bone histology. Recently, a heterozygous mutation in the 5'-untranslated region (UTR) of IFITM5 (c.-14C > T) was identified as the underlying cause of OI type V, and only this specific mutation was subsequently identified in all patient cohorts with this OI subtype. We now present a case of a heterozygous mutation within the coding region of IFITM5 (c.119C > T; p.S40L). The mutation occurred de novo in the patient and resulted in severe OI with prenatal onset and extreme short stature. At the age of 19 months, the typical clinical hallmarks of OI type V were not present. Our finding has important consequences for the genetic "work-up" of patients suspected to have OI, both in prenatal and in postnatal settings: The entire gene-not only the 5'-UTR harboring the "classical" OI type V mutation-has to be analyzed to exclude a causal role of IFITM5. We propose that this should be part of the initial diagnostic steps for genetic laboratories performing SANGER sequencing in OI patients.


Assuntos
Proteínas de Membrana/genética , Mutação/genética , Fases de Leitura Aberta/genética , Osteogênese Imperfeita/genética , Diagnóstico Pré-Natal , Sequência de Aminoácidos , Sequência de Bases , Biologia Computacional , Progressão da Doença , Humanos , Recém-Nascido , Proteínas de Membrana/química , Dados de Sequência Molecular
15.
Am J Med Genet A ; 161A(9): 2158-66, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23913520

RESUMO

Loss-of-function mutations of NSD1 and 5q35 microdeletions encompassing NSD1 are a major cause of Sotos syndrome (Sos), which is characterized by overgrowth, macrocephaly, characteristic facies, and variable intellectual disability (ID). Microduplications of 5q35.2-q35.3 including NSD1 have been reported in only five patients so far and described clinically as a reversed Sos resulting from a hypothetical gene dosage effect of NSD1. Here, we report on nine patients from five families with interstitial duplication 5q35 including NSD1 detected by molecular karyotyping. The clinical features of all 14 individuals are reviewed. Patients with microduplications including NSD1 appear to have a consistent phenotype consisting of short stature, microcephaly, learning disability or mild to moderate ID, and distinctive facial features comprising periorbital fullness, short palpebral fissures, a long nose with broad or long nasal tip, a smooth philtrum and a thin upper lip vermilion. Behavioral problems, ocular and minor hand anomalies may be associated. Based on our findings, we discuss the possible etiology and conclude that it is possible, but so far unproven, that a gene dosage effect of NSD1 may be the major cause.


Assuntos
Duplicação Cromossômica , Cromossomos Humanos Par 5 , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas Nucleares/genética , Fenótipo , Síndrome de Sotos/diagnóstico , Síndrome de Sotos/genética , Adolescente , Adulto , Criança , Pré-Escolar , Mapeamento Cromossômico , Hibridização Genômica Comparativa , Facies , Feminino , Dosagem de Genes , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Adulto Jovem
16.
Eur J Med Genet ; 56(8): 458-62, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23811035

RESUMO

Distal deletion 9p is associated with gonadal dysfunction in XY individuals. Little is known about the gonadal function and fertility of XX females with this condition. We report on an affected 31-year-old infertile woman presenting with premature ovarian failure, mild dysmorphic features, a history of mild developmental delay and an otherwise normal female phenotype. Cytogenetic analysis showed a deletion 9p with the karyotype 46,XX,del(9)(p23-24) in lymphocytes. The subsequent oligonucleotide array-based CGH analysis with genomic DNA from peripheral blood revealed a terminal deletion of approximately 7.6 Mb. SNP microarray analyses of the patient and her unaffected parents confirmed the deletion breakpoint and revealed a de novo mutation of paternal origin. This is apparently the first description of an adult woman with a cytogenetically visible terminal deletion of chromosome 9p. The fertility problems observed in this patient complement earlier findings in prepubertal and pubertal 46,XX-girls with 9p deletions, who displayed a phenotype ranging from primary ovarian dysfunction and mild gonadotropin hyperresponses to positive menses. DMRT1 is hemizygous in our patient. We discuss the role of DMRT1 in female gonadal development.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 9 , Insuficiência Ovariana Primária/diagnóstico , Insuficiência Ovariana Primária/genética , Adulto , Bandeamento Cromossômico , Hibridização Genômica Comparativa , Feminino , Humanos
17.
Am J Hum Genet ; 92(4): 565-74, 2013 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-23499309

RESUMO

We report that hypofunctional alleles of WNT1 cause autosomal-recessive osteogenesis imperfecta, a congenital disorder characterized by reduced bone mass and recurrent fractures. In consanguineous families, we identified five homozygous mutations in WNT1: one frameshift mutation, two missense mutations, one splice-site mutation, and one nonsense mutation. In addition, in a family affected by dominantly inherited early-onset osteoporosis, a heterozygous WNT1 missense mutation was identified in affected individuals. Initial functional analysis revealed that altered WNT1 proteins fail to activate canonical LRP5-mediated WNT-regulated ß-catenin signaling. Furthermore, osteoblasts cultured in vitro showed enhanced Wnt1 expression with advancing differentiation, indicating a role of WNT1 in osteoblast function and bone development. Our finding that homozygous and heterozygous variants in WNT1 predispose to low-bone-mass phenotypes might advance the development of more effective therapeutic strategies for congenital forms of bone fragility, as well as for common forms of age-related osteoporosis.


Assuntos
Densidade Óssea/genética , Osso e Ossos/patologia , Mutação/genética , Osteogênese Imperfeita/genética , Osteoporose/genética , Proteína Wnt1/genética , Animais , Sequência de Bases , Células Cultivadas , Criança , Pré-Escolar , Feminino , Heterozigoto , Humanos , Recém-Nascido , Proteínas Relacionadas a Receptor de LDL/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Osteoblastos/metabolismo , Osteoblastos/patologia , Osteogênese Imperfeita/patologia , Osteoporose/patologia , Linhagem , Fenótipo , Gravidez
19.
Am J Hum Genet ; 91(2): 349-57, 2012 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-22863195

RESUMO

Osteogenesis imperfecta (OI) is a clinically and genetically heterogeneous disorder associated with bone fragility and susceptibility to fractures after minimal trauma. OI type V has an autosomal-dominant pattern of inheritance and is not caused by mutations in the type I collagen genes COL1A1 and COL1A2. The most remarkable and pathognomonic feature, observed in ~65% of affected individuals, is a predisposition to develop hyperplastic callus after fractures or surgical interventions. To identify the molecular cause of OI type V, we performed whole-exome sequencing in a female with OI type V and her unaffected parents and searched for de novo mutations. We found a heterozygous de novo mutation in the 5'-untranslated region of IFITM5 (the gene encoding Interferon induced transmembrane protein 5), 14 bp upstream of the annotated translation initiation codon (c.-14C>T). Subsequently, we identified an identical heterozygous de novo mutation in a second individual with OI type V by Sanger sequencing, thereby confirming that this is the causal mutation for the phenotype. IFITM5 is a protein that is highly enriched in osteoblasts and has a putative function in bone formation and osteoblast maturation. The mutation c.-14C>T introduces an upstream start codon that is in frame with the reference open-reading frame of IFITM5 and is embedded into a stronger Kozak consensus sequence for translation initiation than the annotated start codon. In vitro, eukaryotic cells were able to recognize this start codon, and they used it instead of the reference translation initiation signal. This suggests that five amino acids (Met-Ala-Leu-Glu-Pro) are added to the N terminus and alter IFITM5 function in individuals with the mutation.


Assuntos
Proteínas de Membrana/genética , Osteogênese Imperfeita/genética , Regiões 5' não Traduzidas/genética , Absorciometria de Fóton , Sequência de Aminoácidos , Sequência de Bases , Criança , Códon de Iniciação/genética , Biologia Computacional , Difosfonatos/uso terapêutico , Exoma/genética , Feminino , Humanos , Lactente , Dados de Sequência Molecular , Osteogênese Imperfeita/diagnóstico por imagem , Osteogênese Imperfeita/tratamento farmacológico , Mutação Puntual/genética , Análise de Sequência de DNA
20.
Am J Hum Genet ; 90(4): 661-74, 2012 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-22482805

RESUMO

Bone morphogenetic protein 1 (BMP1) is an astacin metalloprotease with important cellular functions and diverse substrates, including extracellular-matrix proteins and antagonists of some TGFß superfamily members. Combining whole-exome sequencing and filtering for homozygous stretches of identified variants, we found a homozygous causative BMP1 mutation, c.34G>C, in a consanguineous family affected by increased bone mineral density and multiple recurrent fractures. The mutation is located within the BMP1 signal peptide and leads to impaired secretion and an alteration in posttranslational modification. We also characterize a zebrafish bone mutant harboring lesions in bmp1a, demonstrating conservation of BMP1 function in osteogenesis across species. Genetic, biochemical, and histological analyses of this mutant and a comparison to a second, similar locus reveal that Bmp1a is critically required for mature-collagen generation, downstream of osteoblast maturation, in bone. We thus define the molecular and cellular bases of BMP1-dependent osteogenesis and show the importance of this protein for bone formation and stability.


Assuntos
Proteína Morfogenética Óssea 1/fisiologia , Osteogênese/genética , Osteogênese/fisiologia , Animais , Sequência de Bases , Conservadores da Densidade Óssea/uso terapêutico , Proteína Morfogenética Óssea 1/genética , Proteína Morfogenética Óssea 1/metabolismo , Osso e Ossos/metabolismo , Diferenciação Celular , Pré-Escolar , Colágeno/biossíntese , Difosfonatos/uso terapêutico , Exoma , Feminino , Fraturas Ósseas/tratamento farmacológico , Fraturas Ósseas/prevenção & controle , Loci Gênicos , Proteínas de Choque Térmico , Humanos , Masculino , Dados de Sequência Molecular , Mutação , Osteoblastos/efeitos dos fármacos , Osteoblastos/fisiologia , Osteogênese/efeitos dos fármacos , Fragmentos de Peptídeos , Processamento de Proteína Pós-Traducional , Peixe-Zebra/genética , Peixe-Zebra/metabolismo
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