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1.
Am J Hum Genet ; 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31587868

RESUMO

NKAP is a ubiquitously expressed nucleoplasmic protein that is currently known as a transcriptional regulatory molecule via its interaction with HDAC3 and spliceosomal proteins. Here, we report a disorder of transcriptional regulation due to missense mutations in the X chromosome gene, NKAP. These mutations are clustered in the C-terminal region of NKAP where NKAP interacts with HDAC3 and post-catalytic spliceosomal complex proteins. Consistent with a role for the C-terminal region of NKAP in embryogenesis, nkap mutant zebrafish with a C-terminally truncated NKAP demonstrate severe developmental defects. The clinical features of affected individuals are highly conserved and include developmental delay, hypotonia, joint contractures, behavioral abnormalities, Marfanoid habitus, and scoliosis. In affected cases, transcriptome analysis revealed the presence of a unique transcriptome signature, which is characterized by the downregulation of long genes with higher exon numbers. These observations indicate the critical role of NKAP in transcriptional regulation and demonstrate that perturbations of the C-terminal region lead to developmental defects in both humans and zebrafish.

2.
Am J Hum Genet ; 105(4): 844-853, 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31585108

RESUMO

Lissencephaly is a severe brain malformation in which failure of neuronal migration results in agyria or pachygyria and in which the brain surface appears unusually smooth. It is often associated with microcephaly, profound intellectual disability, epilepsy, and impaired motor abilities. Twenty-two genes are associated with lissencephaly, accounting for approximately 80% of disease. Here we report on 12 individuals with a unique form of lissencephaly; these individuals come from eight unrelated families and have bi-allelic mutations in APC2, encoding adenomatous polyposis coli protein 2. Brain imaging studies demonstrate extensive posterior predominant lissencephaly, similar to PAFAH1B1-associated lissencephaly, as well as co-occurrence of subcortical heterotopia posterior to the caudate nuclei, "ribbon-like" heterotopia in the posterior frontal region, and dysplastic in-folding of the mesial occipital cortex. The established role of APC2 in integrating the actin and microtubule cytoskeletons to mediate cellular morphological changes suggests shared function with other lissencephaly-encoded cytoskeletal proteins such as α-N-catenin (CTNNA2) and platelet-activating factor acetylhydrolase 1b regulatory subunit 1 (PAFAH1B1, also known as LIS1). Our findings identify APC2 as a radiographically distinguishable recessive form of lissencephaly.

3.
J Transl Med ; 17(1): 351, 2019 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-31655630

RESUMO

BACKGROUND: Biallelic PTPRQ pathogenic variants have been previously reported as causative for autosomal recessive non-syndromic hearing loss. In 2018 the first heterozygous PTPRQ variant has been implicated in the development of autosomal dominant non-syndromic hearing loss (ADNSHL) in a German family. The study presented the only, so far known, PTPRQ pathogenic variant (c.6881G>A) in ADNSHL. It is located in the last PTPRQ coding exon and introduces a premature stop codon (p.Trp2294*). METHODS: A five-generation Polish family with ADNSHL was recruited for the study (n = 14). Thorough audiological, neurotological and imaging studies were carried out to precisely define the phenotype. Genomic DNA was isolated from peripheral blood samples or buccal swabs of available family members. Clinical exome sequencing was conducted for the proband. Family segregation analysis of the identified variants was performed using Sanger sequencing. Single nucleotide polymorphism array on DNA samples from the Polish and the original German family was used for genome-wide linkage analysis. RESULTS: Combining clinical exome sequencing and family segregation analysis, we have identified the same (NM_001145026.2:c.6881G>A, NP_001138498.1:p.Trp2294*) PTPRQ alteration in the Polish ADNSHL family. Using genome-wide linkage analysis, we found that the studied family and the original German family derive from a common ancestor. Deep phenotyping of the affected individuals showed that in contrast to the recessive form, the PTPRQ-related ADNSHL is not associated with vestibular dysfunction. In both families ADNSHL was progressive, affected mainly high frequencies and had a variable age of onset. CONCLUSION: Our data provide the first confirmation of PTPRQ involvement in ADNSHL. The finding strongly reinforces the inclusion of PTPRQ to the small set of genes leading to both autosomal recessive and dominant hearing loss.

4.
Hum Mol Genet ; 2019 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-31628467

RESUMO

Missense mutations in the RNA exosome component Exosome Component 2 (EXOSC2), also known as Ribosomal RNA-processing Protein 4 (RRP4), were recently identified in two unrelated families with a novel syndrome known as Short stature, Hearing loss, Retinitis pigmentosa, and distinctive Facies (SHRF, #OMIM 617763). Little is known about the mechanism of SHRF pathogenesis. Here we have studied the effect of mutations in EXOSC2/RRP4 in patient-derived lymphoblasts, clustered regularly interspaced short palindromic repeats (CRISPR)-generated mutant fetal keratinocytes, and Drosophila. We determined that human EXOSC2 is an essential gene, and that the pathogenic G198D mutation prevents binding to other RNA exosome components, resulting in protein and complex instability and altered expression and/or activities of critical genes, including those in the autophagy pathway. In parallel, we generated multiple CRISPR knockouts of the fly rrp4 gene. Using these flies, as well as rrp4 mutants with Piggy Bac (PBac) transposon insertion in the 3'UTR and RNAi flies, we determined that fly rrp4 was also essential, that fly rrp4 phenotypes could be rescued by wild-type human EXOSC2 but not the pathogenic form, and that fly rrp4 is critical for eye development and maintenance, muscle ultrastructure, and wing vein development. We found that overexpression of the transcription factor MITF was sufficient to rescue the small eye and adult lethal phenotypes caused by rrp4 inhibition. The autophagy genes ATG1 and ATG17, which are regulated by MITF, had similar effect. Pharmacological stimulation of autophagy with rapamycin also rescued the lethality caused by rrp4 inactivation. Our results implicate defective autophagy in SHRF pathogenesis and suggest therapeutic strategies.

5.
Am J Hum Genet ; 105(1): 213-220, 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31230721

RESUMO

De novo variants represent a significant cause of neurodevelopmental delay and intellectual disability. A genetic basis can be identified in only half of individuals who have neurodevelopmental disorders (NDDs); this indicates that additional causes need to be elucidated. We compared the frequency of de novo variants in patient-parent trios with (n = 2,030) versus without (n = 2,755) NDDs. We identified de novo variants in TAOK1 (thousand and one [TAO] amino acid kinase 1), which encodes the serine/threonine-protein kinase TAO1, in three individuals with NDDs but not in persons who did not have NDDs. Through further screening and the use of GeneMatcher, five additional individuals with NDDs were found to have de novo variants. All eight variants were absent from gnomAD (Genome Aggregation Database). The variant carriers shared a non-specific phenotype of developmental delay, and six individuals had additional muscular hypotonia. We established a fibroblast line of one mutation carrier, and we demonstrated that reduced mRNA levels of TAOK1 could be increased upon cycloheximide treatment. These results indicate nonsense-mediated mRNA decay. Further, there was neither detectable phosphorylated TAO1 kinase nor phosphorylated tau in these cells, and mitochondrial morphology was altered. Knockdown of the ortholog gene Tao1 (Tao, CG14217) in Drosophila resulted in delayed early development. The majority of the Tao1-knockdown flies did not survive beyond the third instar larval stage. When compared to control flies, Tao1 knockdown flies revealed changed morphology of the ventral nerve cord and the neuromuscular junctions as well as a decreased number of endings (boutons). Furthermore, mitochondria in mutant flies showed altered distribution and decreased size in axons of motor neurons. Thus, we provide compelling evidence that de novo variants in TAOK1 cause NDDs.

6.
Epilepsia ; 60(6): e63-e66, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31077350

RESUMO

Severe early onset epilepsies are often caused by de novo pathogenic variants. Few studies have reported the frequency of somatic mosaicism in parents of children with severe epileptic encephalopathies. Here we aim to investigate the frequency of mosaicism in the parents of children with epilepsy caused by alleged de novo variants. We tested parental genomic DNA derived from different tissues for 75 cases using targeted next-generation sequencing. Five parents (6.6%) showed mosaicism at minor allele frequencies of 0.8%-29% for the pathogenic variant detected in their offspring. Parental mosaicism was observed in the following genes: SCN1A, SCN2A, SCN8A, and STXBP1. One of the identified parents had epilepsy himself. Our results show that de novo events can occur already in parental tissue and in some cases can be detected in peripheral blood. Consequently, parents affected by low-grade mosaicism are faced with an increased recurrence risk for transmitting the pathogenic variant, compared to the overall recurrence risk for a second affected child estimated at approximately 1%. However, testing for parental somatic mosaicism will help identifying those parents who truly are at higher risk and will significantly improve genetic counseling in the respective families.

7.
Am J Hum Genet ; 104(2): 203-212, 2019 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-30612693

RESUMO

Using exome sequencing, we have identified de novo variants in MAPK8IP3 in 13 unrelated individuals presenting with an overlapping phenotype of mild to severe intellectual disability. The de novo variants comprise six missense variants, three of which are recurrent, and three truncating variants. Brain anomalies such as perisylvian polymicrogyria, cerebral or cerebellar atrophy, and hypoplasia of the corpus callosum were consistent among individuals harboring recurrent de novo missense variants. MAPK8IP3 has been shown to be involved in the retrograde axonal-transport machinery, but many of its specific functions are yet to be elucidated. Using the CRISPR-Cas9 system to target six conserved amino acid positions in Caenorhabditis elegans, we found that two of the six investigated human alterations led to a significantly elevated density of axonal lysosomes, and five variants were associated with adverse locomotion. Reverse-engineering normalized the observed adverse effects back to wild-type levels. Combining genetic, phenotypic, and functional findings, as well as the significant enrichment of de novo variants in MAPK8IP3 within our total cohort of 27,232 individuals who underwent exome sequencing, we implicate de novo variants in MAPK8IP3 as a cause of a neurodevelopmental disorder with intellectual disability and variable brain anomalies.

8.
Am J Med Genet A ; 176(12): 2862-2866, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30561130

RESUMO

Autosomal recessive keratoderma-ichthyosis-deafness (ARKID) syndrome is a rare multisystem disorder caused by biallelic mutations in VPS33B; only three patients have been reported to date. ARKID syndrome is allelic to arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome (MIM #208085), a severe disorder with early lethality whose phenotypic characteristics also include ichthyosis, hearing loss, severe failure to thrive, platelet dysfunction and osteopenia. We report on an 11-year-old male patient with ARKID syndrome and compound heterozygous VPS33B mutations, one of which [c.1440delG; p.(Arg481Glyfs*11)] was novel. Clinical features of this patient included ichthyosis, palmoplantar keratosis, hearing loss, intellectual disability, unilateral hip dislocation, microcephaly and short stature. He also had copper hepatopathy and exocrine pancreatic insufficiency, features that have so far been associated with neither ARKID nor ARC syndrome. The patient broadens the clinical and molecular spectrum of ARKID syndrome and contributes to genotype-phenotype associations of this rare disorder.


Assuntos
Genes Recessivos , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/genética , Ictiose/diagnóstico , Ictiose/genética , Ceratodermia Palmar e Plantar/diagnóstico , Ceratodermia Palmar e Plantar/genética , Mutação , Proteínas de Transporte Vesicular/genética , Biomarcadores , Criança , Aberrações Cromossômicas , Hibridização Genômica Comparativa , Estudos de Associação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Linhagem , Fenótipo , Síndrome
10.
Nat Commun ; 9(1): 4250, 2018 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-30315159

RESUMO

Germline mutations in the ubiquitously expressed ACTB, which encodes ß-cytoplasmic actin (CYA), are almost exclusively associated with Baraitser-Winter Cerebrofrontofacial syndrome (BWCFF). Here, we report six patients with previously undescribed heterozygous variants clustered in the 3'-coding region of ACTB. Patients present with clinical features distinct from BWCFF, including mild developmental disability, microcephaly, and thrombocytopenia with platelet anisotropy. Using patient-derived fibroblasts, we demonstrate cohort specific changes to ß-CYA filament populations, which include the enhanced recruitment of thrombocytopenia-associated actin binding proteins (ABPs). These perturbed interactions are supported by in silico modeling and are validated in disease-relevant thrombocytes. Co-examination of actin and microtubule cytoskeleton constituents in patient-derived megakaryocytes and thrombocytes indicates that these ß-CYA mutations inhibit the final stages of platelet maturation by compromising microtubule organization. Our results define an ACTB-associated clinical syndrome with a distinct genotype-phenotype correlation and delineate molecular mechanisms underlying thrombocytopenia in this patient cohort.

11.
PLoS One ; 13(8): e0201041, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30091983

RESUMO

Although intellectual disability is one of the major indications for genetic counselling, there are no homogenous diagnostic algorithms for molecular testing. While whole exome sequencing is increasingly applied, we questioned whether analyzing a partial exome, enriched for genes associated with Mendelian disorders, might be a valid alternative approach that yields similar detection rates but requires less sequencing capacities. Within this context 106 patients with different intellectual disability forms were analyzed for mutations in 4.813 genes after pre-exclusion of copy number variations by array-CGH. Subsequent variant interpretation was performed in accordance with the ACMG guidelines. By this, a molecular diagnosis was established in 34% of cases and candidate mutations were identified in additional 24% of patients. Detection rates of causative mutations were above 30%, regardless of further symptoms, except for patients with seizures (23%). We did not detect an advantage from partial exome sequencing for patients with severe intellectual disability (36%) as compared to those with mild intellectual disability (44%). Specific clinical diagnoses pre-existed for 20 patients. Of these, 5 could be confirmed and an additional 6 cases could be solved, but showed mutations in other genes than initially suspected. In conclusion partial exome sequencing solved >30% of intellectual disability cases, which is similar to published rates obtained by whole exome sequencing. The approach therefore proved to be a valid alternative to whole exome sequencing for molecular diagnostics in this cohort. The method proved equally suitable for both syndromic and non-syndromic intellectual disability forms of all severity grades.

12.
Hum Mutat ; 39(9): 1226-1237, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29897170

RESUMO

Malan syndrome is an overgrowth disorder described in a limited number of individuals. We aim to delineate the entity by studying a large group of affected individuals. We gathered data on 45 affected individuals with a molecularly confirmed diagnosis through an international collaboration and compared data to the 35 previously reported individuals. Results indicate that height is > 2 SDS in infancy and childhood but in only half of affected adults. Cardinal facial characteristics include long, triangular face, macrocephaly, prominent forehead, everted lower lip, and prominent chin. Intellectual disability is universally present, behaviorally anxiety is characteristic. Malan syndrome is caused by deletions or point mutations of NFIX clustered mostly in exon 2. There is no genotype-phenotype correlation except for an increased risk for epilepsy with 19p13.2 microdeletions. Variants arose de novo, except in one family in which mother was mosaic. Variants causing Malan and Marshall-Smith syndrome can be discerned by differences in the site of stop codon formation. We conclude that Malan syndrome has a well recognizable phenotype that usually can be discerned easily from Marshall-Smith syndrome but rarely there is some overlap. Differentiation from Sotos and Weaver syndrome can be made by clinical evaluation only.

13.
Eur J Hum Genet ; 26(8): 1132-1142, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29706637

RESUMO

Tubulinopathies are a heterogeneous group of conditions with a wide spectrum of clinical severity resulting from variants in genes of the tubulin superfamily. Variants in TUBG1 have been described in three patients with posterior predominant pachygyria and microcephaly. We here report eight additional patients with four novel heterozygous variants in TUBG1 identified by next-generation sequencing (NGS) analysis. All had severe motor and cognitive impairment and all except one developed seizures in early life. The core imaging features included a pachygyric cortex with posterior to anterior gradient, enlarged lateral ventricles most pronounced over the posterior horns, and variable degrees of reduced white matter volume. Basal ganglia, corpus callosum, brainstem, and cerebellum were often normal, in contrast to patients with variants in other tubulin genes where these structures are frequently malformed. The imaging phenotype associated with variants in TUBG1 is therefore more in line with the phenotype resulting from variants in LIS1 (a.k.a. PAFAH1B1). This difference may, at least in part, be explained by gamma-tubulin's physiological function in microtubule nucleation, which differs from that of alpha and beta-tubulin.

14.
Eur J Med Genet ; 2018 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-29758292

RESUMO

Truncating mutations in the last and penultimate exons of the PPM1D gene were recently described as a cause for mild to severe intellectual disability in fourteen patients. Feeding difficulties, periods of fever and vomiting as well as a high pain threshold were described as additional characteristic features and the disorder was subsequently termed "intellectual developmental disorder with gastrointestinal difficulties and high pain threshold (IDDGIP)" in the OMIM database (MIM # 617450). Here we report on an additional patient carrying a novel de novo truncating mutation NM_003620.3: c.1535del, p.(Asn512Ilefs*2) in the last exon of PPM1D. While the patient showed features overlapping with the reported phenotype, such as a short stature and small hands and feet, he also presented with additional features like cleft lip and palate and an aberrant right subclavian artery. Notably, the patient did not have any gastrointestinal difficulties or periods of fever, indicating variability of the phenotype of patients with PPM1D mutations.

15.
Genet Med ; 20(11): 1354-1364, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29671837

RESUMO

PURPOSE: To estimate diagnostic yield and genotype-phenotype correlations in a cohort of 811 patients with lissencephaly or subcortical band heterotopia. METHODS: We collected DNA from 756 children with lissencephaly over 30 years. Many were tested for deletion 17p13.3 and mutations of LIS1, DCX, and ARX, but few other genes. Among those tested, 216 remained unsolved and were tested by a targeted panel of 17 genes (ACTB, ACTG1, ARX, CRADD, DCX, LIS1, TUBA1A, TUBA8, TUBB2B, TUBB, TUBB3, TUBG1, KIF2A, KIF5C, DYNC1H1, RELN, and VLDLR) or by whole-exome sequencing. Fifty-five patients studied at another institution were added as a validation cohort. RESULTS: The overall mutation frequency in the entire cohort was 81%. LIS1 accounted for 40% of patients, followed by DCX (23%), TUBA1A (5%), and DYNC1H1 (3%). Other genes accounted for 1% or less of patients. Nineteen percent remained unsolved, which suggests that several additional genes remain to be discovered. The majority of unsolved patients had posterior pachygyria, subcortical band heterotopia, or mild frontal pachygyria. CONCLUSION: The brain-imaging pattern correlates with mutations in single lissencephaly-associated genes, as well as in biological pathways. We propose the first LIS classification system based on the underlying molecular mechanisms.

16.
Genet Med ; 20(6): 614-621, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29309402

RESUMO

PurposeHearing loss is genetically extremely heterogeneous, making it suitable for next-generation sequencing (NGS). We identified a four-generation family with nonsyndromic mild to severe hearing loss of the mid- to high frequencies and onset from early childhood to second decade in seven members.MethodsNGS of 66 deafness genes, Sanger sequencing, genome-wide linkage analysis, whole-exome sequencing (WES), semiquantitative reverse-transcriptase polymerase chain reaction.ResultsWe identified a heterozygous nonsense mutation, c.6881G>A (p.Trp2294*), in the last coding exon of PTPRQ. PTPRQ has been linked with recessive (DFNB84A), but not dominant deafness. NGS and Sanger sequencing of all exons (including alternatively spliced 5' and N-scan-predicted exons of a putative "extended" transcript) did not identify a second mutation. The highest logarithm of the odds score was in the PTPRQ-containing region on chromosome 12, and p.Trp2294* cosegregated with hearing loss. WES did not identify other cosegregating candidate variants from the mapped region. PTPRQ expression in patient fibroblasts indicated that the mutant allele escapes nonsense-mediated decay (NMD).ConclusionKnown PTPRQ mutations are recessive and do not affect the C-terminal exon. In contrast to recessive loss-of-function mutations, c.6881G>A transcripts may escape NMD. PTPRQTrp2294* protein would lack only six terminal residues and could exert a dominant-negative effect, a possible explanation for allelic deafness, DFNA73, clinically and genetically distinct from DFNB84A.


Assuntos
Surdez/genética , Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/genética , Sequência de Aminoácidos , Códon sem Sentido/genética , Exoma/genética , Éxons/genética , Família , Feminino , Ligação Genética , Estudo de Associação Genômica Ampla , Perda Auditiva/genética , Humanos , Masculino , Mutação , Linhagem , Sequenciamento Completo do Exoma
17.
Eur J Paediatr Neurol ; 22(1): 186-189, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29221912

RESUMO

Aicardi-Goutières syndrome (AGS) is a hereditary inflammatory encephalopathy resulting in severe neurological damage in the majority of cases. We report on two siblings with AGS6 due to compound heterozygosity for a known and a novel mutation in the ADAR gene and a strikingly variable phenotype. The first sibling presented at 12 months of age with a subacute encephalopathy following a mild respiratory infection. The child developed a spastic tetraparesis, generalized dystonia and dysarthria. In contrast, the younger sibling presented with an acute episode of neurological impairment in his third year of life, from which he recovered without sequelae within a few weeks. These findings illustrate a striking intrafamilial phenotypic variability in patients with AGS6 and describe the first case of a full recovery from an acute encephalopathy in an AGS patient. Our findings also suggest that AGS should be considered as an important differential diagnosis of an infection-triggered encephalopathy in infancy despite the absence of typical neuroimaging findings.


Assuntos
Adenosina Desaminase/genética , Doenças Autoimunes do Sistema Nervoso/diagnóstico , Doenças Autoimunes do Sistema Nervoso/genética , Malformações do Sistema Nervoso/diagnóstico , Malformações do Sistema Nervoso/genética , Proteínas de Ligação a RNA/genética , Adolescente , Pré-Escolar , Feminino , Humanos , Masculino , Mutação , Fenótipo
18.
Am J Med Genet A ; 173(9): 2545-2550, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28777483

RESUMO

Mutations in DLG3 are a rare cause of non-syndromic X-linked intellectual disability (XLID) (MRX90, OMIM *300189). Only ten DLG3 mutations have been reported to date. The majority of female heterozygous mutation carriers was healthy and had random X-inactivation patterns. We report on an XLID family with a novel DLG3 mutation. The 12-year-old male index patient had moderate intellectual disability (ID) and dysmorphic features. The mutation was also present in four female relatives. A maternal aunt had moderate ID and significantly skewed X-inactivation favorably inactivating the normal DLG3 allele. The proband's healthy mother also had skewed X-inactivation but in the opposite direction (i.e., inactivation of the mutated allele). Two other female relatives had intermediate cognitive phenotypes and random X-inactivation. This family broadens the mutational and phenotypical spectrum of DLG3-associated XLID and demonstrates that heterozygous female mutation carriers can be as severely affected as males. Reports of additional families will be needed to elucidate the causes of unfavorable skewing in female XLID patients.


Assuntos
Doenças Genéticas Ligadas ao Cromossomo X/genética , Deficiência Intelectual/genética , Retardo Mental Ligado ao Cromossomo X/genética , Proteínas Nucleares/genética , Fatores de Transcrição/genética , Cromossomos Humanos X/genética , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/fisiopatologia , Heterozigoto , Humanos , Deficiência Intelectual/fisiopatologia , Masculino , Retardo Mental Ligado ao Cromossomo X/fisiopatologia , Mutação , Linhagem , Inativação do Cromossomo X/genética
19.
Am J Med Genet A ; 173(10): 2736-2742, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28742244

RESUMO

Phosphoribosylpyrophosphate synthetase (PRPPS) superactivity (OMIM 300661) is a rare inborn error of purine metabolism that is caused by gain-of-function mutations in the X-chromosomal gene PRPS1 (Xq22.3). Clinical characteristics include congenital hyperuricemia and hyperuricosuria, gouty arthritis, urolithiasis, developmental delay, hypotonia, recurrent infections, short stature, and hearing loss. Only eight families with PRPPS superactivity and PRPS1 gain-of-function mutations have been reported to date. We report on a 7-year-old boy with congenital hyperuricemia, urolithiasis, developmental delay, short stature, hypospadias, and facial dysmorphisms. His mother also suffered from hyperuricemia that was diagnosed at age 13 years. A novel PRPS1 missense mutation (c.573G>C, p.[Leu191Phe]) was detected in the proband and his mother. Enzyme activity analysis confirmed superactivity of PRPP synthetase. Analysis of the crystal structure of human PRPPS suggests that the Leu191Phe mutation affects the architecture of both allosteric sites, thereby preventing the allosteric inhibition of the enzyme. The family reported here broadens the clinical spectrum of PRPPS superactivity and indicates that this rare metabolic disorder might be associated with a recognizable facial gestalt.


Assuntos
Face/anormalidades , Mutação com Ganho de Função , Hiperuricemia/congênito , Hiperuricemia/genética , Ribose-Fosfato Pirofosfoquinase/genética , Criança , Face/patologia , Humanos , Hiperuricemia/patologia , Masculino , Erros Inatos do Metabolismo da Purina-Pirimidina/genética , Erros Inatos do Metabolismo da Purina-Pirimidina/metabolismo , Ribose-Fosfato Pirofosfoquinase/metabolismo
20.
J Med Genet ; 54(9): 613-623, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28735298

RESUMO

BACKGROUND: Mutations in forkhead box protein P1 (FOXP1) cause intellectual disability (ID) and specific language impairment (SLI), with or without autistic features (MIM: 613670). Despite multiple case reports no specific phenotype emerged so far. METHODS: We correlate clinical and molecular data of 25 novel and 23 previously reported patients with FOXP1 defects. We evaluated FOXP1 activity by an in vitro luciferase model and assessed protein stability in vitro by western blotting. RESULTS: Patients show ID, SLI, neuromotor delay (NMD) and recurrent facial features including a high broad forehead, bent downslanting palpebral fissures, ptosis and/or blepharophimosis and a bulbous nasal tip. Behavioural problems and autistic features are common. Brain, cardiac and urogenital malformations can be associated. More severe ID and NMD, sensorineural hearing loss and feeding difficulties are more common in patients with interstitial 3p deletions (14 patients) versus patients with monogenic FOXP1 defects (34 patients). Mutations result in impaired transcriptional repression and/or reduced protein stability. CONCLUSIONS: FOXP1-related ID syndrome is a recognisable entity with a wide clinical spectrum and frequent systemic involvement. Our data will be helpful to evaluate genotype-phenotype correlations when interpreting next-generation sequencing data obtained in patients with ID and/or SLI and will guide clinical management.


Assuntos
Fatores de Transcrição Forkhead/genética , Deficiência Intelectual/genética , Proteínas Repressoras/genética , Transtorno do Espectro Autista/genética , Face/anormalidades , Feminino , Fatores de Transcrição Forkhead/química , Fatores de Transcrição Forkhead/metabolismo , Humanos , Transtornos da Linguagem/genética , Masculino , Transtornos das Habilidades Motoras/genética , Mutação , Mutação de Sentido Incorreto , Transtornos do Neurodesenvolvimento/genética , Fenótipo , Estabilidade Proteica , Proteínas Repressoras/química , Proteínas Repressoras/metabolismo , Síndrome , Transcrição Genética
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