-
Nucleic Acids Research Sep 2019Expression of human mitochondrial DNA is indispensable for proper function of the oxidative phosphorylation machinery. The mitochondrial genome encodes 22 tRNAs, 2 rRNAs...
Expression of human mitochondrial DNA is indispensable for proper function of the oxidative phosphorylation machinery. The mitochondrial genome encodes 22 tRNAs, 2 rRNAs and 11 mRNAs and their post-transcriptional modification constitutes one of the key regulatory steps during mitochondrial gene expression. Cytosine-5 methylation (m5C) has been detected in mitochondrial transcriptome, however its biogenesis has not been investigated in details. Mammalian NOP2/Sun RNA Methyltransferase Family Member 2 (NSUN2) has been characterized as an RNA methyltransferase introducing m5C in nuclear-encoded tRNAs, mRNAs and microRNAs and associated with cell proliferation and differentiation, with pathogenic variants in NSUN2 being linked to neurodevelopmental disorders. Here we employ spatially restricted proximity labelling and immunodetection to demonstrate that NSUN2 is imported into the matrix of mammalian mitochondria. Using three genetic models for NSUN2 inactivation-knockout mice, patient-derived fibroblasts and CRISPR/Cas9 knockout in human cells-we show that NSUN2 is necessary for the generation of m5C at positions 48, 49 and 50 of several mammalian mitochondrial tRNAs. Finally, we show that inactivation of NSUN2 does not have a profound effect on mitochondrial tRNA stability and oxidative phosphorylation in differentiated cells. We discuss the importance of the newly discovered function of NSUN2 in the context of human disease.
Topics: 5-Methylcytosine; Animals; CRISPR-Cas Systems; Eczema; Facies; Fibroblasts; Gene Editing; Gene Knockout Techniques; Growth Disorders; HEK293 Cells; Humans; Intellectual Disability; Methylation; Methyltransferases; Mice; Mice, Knockout; Microcephaly; Mitochondria; Nucleic Acid Conformation; Oxidative Phosphorylation; Primary Cell Culture; Protein Transport; RNA Processing, Post-Transcriptional; RNA, Messenger; RNA, Mitochondrial; RNA, Transfer
PubMed: 31276587
DOI: 10.1093/nar/gkz559 -
European Journal of Anaesthesiology Aug 2019
PubMed: 31274551
DOI: 10.1097/EJA.0000000000000959 -
American Journal of Medical Genetics.... Dec 2018Due to the efforts of the clinical and scientific communities and boosted by recent advances in genetic technologies, we now understand the molecular mechanisms...
Due to the efforts of the clinical and scientific communities and boosted by recent advances in genetic technologies, we now understand the molecular mechanisms underlying most of the frequent and recognizable human malformation syndromes. However, some well-established human malformation syndromes remain without a molecular diagnosis despite intensive investigation. This issue of Seminars mines the phenotypic entries in OMIM and estimates that of the documented 2,034 unsolved entries likely to represent a rare genetic disease, only 160 are well-established and possibly amenable to investigation. This issue also reviews well-characterized and extensively investigated human malformation syndromes and associations that remain unsolved, including the following: Dubowitz syndrome (MIM 223370%), Hallermann-Streiff syndrome (MIM 234100%), PHACE syndrome (MIM 606519), Oculocerebrocutaneous syndrome (MIM 164180), Aicardi syndrome (MIM 304050%), Gomez-Lopez-Hernandez syndrome and Rhombencephalosynapsis (MIM 601853%), VACTERL (MIM 192350%), and Nablus syndrome (MIM #608156). Possible explanations for their intractability to molecular diagnosis are explored, including genetic and phenotypic heterogeneity, mosaicism, epigenetics, gene-environment interactions, and other non-Mendelian contributions. Finally, this issue of Seminars presents a path forward for these unsolved rare conditions and suggests a renewed focus on solving amendable OMIM disorders. It is clear that the way forward will require new technologies, global cooperation, and data sharing; these will also be necessary to help reach the vision of the International Rare Diseases Research Consortium (IRDiRC), that is to enable all people living with a rare disease to receive an accurate diagnosis, care and available therapy within 1 year of coming to medical attention.
Topics: Abnormalities, Multiple; Alopecia; Cerebellar Diseases; Cerebellum; Craniofacial Abnormalities; Eczema; Facies; Growth Disorders; Humans; Intellectual Disability; Microcephaly; Neurocutaneous Syndromes; Rare Diseases; Rhombencephalon; Syndrome
PubMed: 30580485
DOI: 10.1002/ajmg.c.31665 -
American Journal of Medical Genetics.... Dec 2018Dubowitz syndrome was described in 1965 as a recognizable syndrome characterized by microcephaly, short stature, eczema, mild developmental delays, and an increased risk...
Dubowitz syndrome was described in 1965 as a recognizable syndrome characterized by microcephaly, short stature, eczema, mild developmental delays, and an increased risk of malignancy. Since its original description, there have been over 200 reported cases though no single gene has been identified to explain a significant proportion of affected individuals. Since the last definitive review of Dubowitz syndrome in 1996, there have been 63 individuals with a clinical, or suspected, diagnosis of Dubowitz syndrome reported in 51 publications. These individuals show a markedly wide spectrum with respect to growth, facial gestalt, psychomotor development, and risk of malignancy; genetic causes were identified in 33% (21/63). Seven individuals had deleterious copy number variants, in particular deletions at 14q32 and 17q24 were reported and showed overlap with the Dubowitz phenotype. Several cases were shown to have single gene disorders that included de novo or biallelic pathogenic variants in several genes including NSUN2 and LIG4 frequently identified by next-generation sequencing methods. It appears that the inability to identify a single gene responsible for Dubowitz syndrome reflects its extreme clinical and genetic heterogeneity. However, detailed phenotyping combined with careful grouping of subsets of unsolved cases and in conjunction with data-sharing will identify novel disease genes responsible for additional cases. In the interim, for those clinically diagnosed with a Dubowitz phenotype, we recommend assessment by a Medical Geneticist, a microarray and, if available, clinical or research based genome-wide sequencing. Management suggestions, including decisions regarding malignancy screening in select patients will be discussed.
Topics: Child; Disease Management; Eczema; Facies; Female; Genetic Heterogeneity; Growth Disorders; Humans; Intellectual Disability; Male; Meta-Analysis as Topic; Microcephaly; Phenotype; Prognosis
PubMed: 30580484
DOI: 10.1002/ajmg.c.31661 -
American Journal of Medical Genetics.... Jan 2019
Topics: Abnormalities, Multiple; Child, Preschool; Eczema; Facies; Female; Growth Disorders; Humans; Infant; Infant, Newborn; Intellectual Disability; Microcephaly; RNA Splicing Factors; Repressor Proteins
PubMed: 30569551
DOI: 10.1002/ajmg.a.60691 -
Dermatology (Basel, Switzerland) 2018Keloids are benign fibroproliferative tumors that extend beyond the original wound. Spontaneous keloids are those that result without a significant history of trauma.... (Review)
Review
BACKGROUND
Keloids are benign fibroproliferative tumors that extend beyond the original wound. Spontaneous keloids are those that result without a significant history of trauma. There are multiple reported cases in the literature.
OBJECTIVE
This article provides a summary and review of the cases that have been reported with spontaneous keloids and organizes them according to their associated medical conditions.
METHODS
A literature review was conducted using PubMed and MEDLINE that included all English published cases and case series from May 1955 to February 2018.
RESULTS
Spontaneous keloids have been reported mainly in association with syndromes such as Rubinstein-Taybi syndrome, Dubowitz syndrome, Noonan syndrome, Goeminne syndrome, Bethlem myopathy, conjunctivocorneal dystrophy, X-linked recessive polyfibromatosis and a novel X-linked syndrome with flamin A mutation. Furthermore, spontaneous keloids were reported in atopic patients and a couple of patients who are medically healthy.
CONCLUSION
Spontaneous keloids are diagnosed clinically based on the patient's history, and it is challenging to confirm since they might be triggered by minimal injury or inflammation especially if it is a single lesion. Reported syndromes indicate a genetic possibility in the pathogenesis of spontaneous keloids.
Topics: Humans; Keloid
PubMed: 30114700
DOI: 10.1159/000491924 -
American Journal of Medical Genetics.... Jun 2018Microdeletions of 17q24.2-q24.3 have been described in several patients with developmental and speech delay, growth retardation, and other features. The relatively large...
Microdeletions of 17q24.2-q24.3 have been described in several patients with developmental and speech delay, growth retardation, and other features. The relatively large size and limited overlap of the deletions complicate the genotype-phenotype correlation. We identified a girl with intellectual disability, growth retardation, dysmorphic features, and a de novo 2.8 Mb long deletion of 17q24.2-q24.3. Her phenotype was strikingly similar to one previously described boy with Dubowitz syndrome (MIM 223370) and a de novo 3.9 Mb long deletion encompassing the deletion of our patient. In addition, both patients had the shortest telomeres among normal age-matched controls. Our review of all 17q24.2-q24.3 deletion patients revealed additional remarkable phenotypic features shared by the patients, some of which have consequences for their management. Proposed novel genotype-phenotype correlations based on new literature information on the region include the role of PSMD12 and BPTF, the genes recently associated with syndromic neurodevelopmental disorders, and a possible role of the complex topologically associated domain structure of the region, which may explain some of the phenotypic discrepancies observed between patients with similar but not identical deletions. Nevertheless, although different diagnoses including the Dubowitz, Nijmegen breakage (MIM 251260), Silver-Russell (MIM 180860), or Myhre (MIM 139210) syndromes were originally considered in the 17q24.2-q24.3 deletion patients, they clearly belong to one diagnostic entity defined by their deletions and characterized especially by developmental delay, specific facial dysmorphism, abnormalities of extremities and other phenotypes, and possibly also short telomere length.
Topics: Child; Chromosome Deletion; Chromosomes, Human, Pair 17; Developmental Disabilities; Eczema; Face; Facies; Female; Fibromatosis, Gingival; Growth Disorders; Humans; Hypertrichosis; Intellectual Disability; Microcephaly; Phenotype; Telomere
PubMed: 29696806
DOI: 10.1002/ajmg.a.38711 -
American Journal of Medical Genetics.... Jul 2017Developmental encephalopathies constitute a broad and genetically heterogeneous spectrum of disorders associated with global developmental delay, intellectual...
Developmental encephalopathies constitute a broad and genetically heterogeneous spectrum of disorders associated with global developmental delay, intellectual disability, frequent epilepsy, and other neurofunctional abnormalities. Here, we report a male presenting with infantile onset epilepsy and syndromic features resembling Dubowitz syndrome identified to have a de novo PLXNA1 variant by whole exome sequencing. This constitutes the second report of PLXNA1 sequence variation associated with early onset epilepsy, and the first to expand on the clinical features of this emerging disorder. This reports suggests that nonsynonymous de novo sequence variations in PLXNA1 are associated with a novel human phenotype characterized by intractable early onset epilepsy, intellectual disability, and syndromic features.
PubMed: 28464511
DOI: 10.1002/ajmg.a.38236 -
Journal of Human Genetics Apr 2017Kaufman oculo-cerebro-facial syndrome (KOS) is caused by recessive UBE3B mutations and presents with microcephaly, ocular abnormalities, distinctive facial morphology,...
Kaufman oculo-cerebro-facial syndrome (KOS) is caused by recessive UBE3B mutations and presents with microcephaly, ocular abnormalities, distinctive facial morphology, low cholesterol levels and intellectual disability. We describe a child with microcephaly, brachycephaly, hearing loss, ptosis, blepharophimosis, hypertelorism, cleft palate, multiple renal cysts, absent nails, small or absent terminal phalanges, absent speech and intellectual disability. Syndromes that were initially considered include DOORS syndrome, Coffin-Siris syndrome and Dubowitz syndrome. Clinical investigations coupled with karyotype analysis, array-comparative genomic hybridization, exome and Sanger sequencing were performed to characterize the condition in this child. Sanger sequencing was negative for the DOORS syndrome gene TBC1D24 but exome sequencing identified a homozygous deletion in UBE3B (NM_183415:c.3139_3141del, p.1047_1047del) located within the terminal portion of the HECT domain. This finding coupled with the presence of characteristic features such as brachycephaly, ptosis, blepharophimosis, hypertelorism, short palpebral fissures, cleft palate and developmental delay allowed us to make a diagnosis of KOS. In conclusion, our findings highlight the importance of considering KOS as a differential diagnosis for patients under evaluation for DOORS syndrome and expand the phenotype of KOS to include small or absent terminal phalanges, nails, and the presence of hallux varus and multicystic dysplastic kidneys.
Topics: Abnormalities, Multiple; Adult; Carrier Proteins; Child; Child, Preschool; Diagnosis, Differential; Eczema; Eye Abnormalities; Face; Facies; Female; GTPase-Activating Proteins; Growth Disorders; Hand Deformities, Congenital; Humans; Intellectual Disability; Karyotype; Limb Deformities, Congenital; Male; Membrane Proteins; Microcephaly; Micrognathism; Mutation; Neck; Nerve Tissue Proteins; Pathology, Molecular; Sequence Analysis, DNA; Ubiquitin-Protein Ligases
PubMed: 28003643
DOI: 10.1038/jhg.2016.151 -
Haematologica Oct 2016Dyskeratosis congenita is a highly pleotropic genetic disorder. This heterogeneity can lead to difficulties in making an accurate diagnosis and delays in appropriate...
Dyskeratosis congenita is a highly pleotropic genetic disorder. This heterogeneity can lead to difficulties in making an accurate diagnosis and delays in appropriate management. The aim of this study was to determine the underlying genetic basis in patients presenting with features of dyskeratosis congenita and who were negative for mutations in the classical dyskeratosis congenita genes. By whole exome and targeted sequencing, we identified biallelic variants in genes that are not associated with dyskeratosis congenita in 17 individuals from 12 families. Specifically, these were homozygous variants in USB1 (8 families), homozygous missense variants in GRHL2 (2 families) and identical compound heterozygous variants in LIG4 (2 families). All patients had multiple somatic features of dyskeratosis congenita but not the characteristic short telomeres. Our case series shows that biallelic variants in USB1, LIG4 and GRHL2, the genes mutated in poikiloderma with neutropenia, LIG4/Dubowitz syndrome and the recently recognized ectodermal dysplasia/short stature syndrome, respectively, cause features that overlap with dyskeratosis congenita. Strikingly, these genes also overlap in their biological function with the known dyskeratosis congenita genes that are implicated in telomere maintenance and DNA repair pathways. Collectively, these observations demonstrate the marked overlap of dyskeratosis congenita with four other genetic syndromes, confounding accurate diagnosis and subsequent management. This has important implications for establishing a genetic diagnosis when a new patient presents in the clinic. Patients with clinical features of dyskeratosis congenita need to have genetic analysis of USB1, LIG4 and GRHL2 in addition to the classical dyskeratosis congenita genes and telomere length measurements.
Topics: DNA Ligase ATP; DNA-Binding Proteins; Dyskeratosis Congenita; Exome; Genetic Variation; Humans; Pedigree; Phosphoric Diester Hydrolases; Sequence Analysis, DNA; Syndrome; Transcription Factors
PubMed: 27612988
DOI: 10.3324/haematol.2016.147769