Advances in the genetics of congenital ptosis

Congenital ptosis, a birth defects presents at birth or by 1 year of age, is characterized by the drooping of the upper eyelid. either in isolation (non-syndromic) or with many different systemic disorders (syndromic). The estimated prevalence of ptosis (congenital & acquired) ranges from 0.79 to 1.99 per 10,000 people in different populations, and it is more prevalent in males. The underlying pathogenesis of congenital ptosis are myogenic and neurogenic, related to the development of muscles and nerves. Although most cases are sporadic, there are familial transmission characteristics, including autosomal dominant, recessive mode and X-linkage inheritance patterns. Moreover, some forms are due to chromosomal aberrations and mutations and deletions in mitochondrial DNA. Genes involved in simple congenital ptosis are ZFHX4 and COL25A1. The clinical aspects of various syndromes involving congenital ptosis are partly caused by single gene mutations. However, the pathogenesis of congenital ptosis is not fully understood. We review the reported epidemiology, genetics and clinical features of congenital ptosis and associated syndromes here.

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Tuberous Sclerosis and Autism

10.1093/med/9780199744312.003.0009 ◽

2013 ◽

Author(s):

Dan Ehninger ◽

Alcino J. Silva

Keyword(s):

Tuberous Sclerosis ◽

Autosomal Dominant ◽

De Novo ◽

Single Gene ◽

Gene Mutations ◽

Extended Version ◽

Single Gene Disorder ◽

Autosomal Dominant Pattern ◽

Organ Systems ◽

The Brain

Tuberous sclerosis (TSC) is a single-gene disorder caused by heterozygous mutations in either the TSC1 or TSC2 genes (Consortium, 1993; van Slegtenhorst et al., 1997). In 70% of cases, TSC gene mutations arise de novo. The remaining 30% of cases are familial with an autosomal dominant pattern of inheritance. Tuberous sclerosis belongs to the group of phakomatoses (neurocutaneous disorders) and is associated with characteristic manifestations in various organ systems, including the brain, skin, kidney, lung, heart, and liver (Crino, Nathanson, & Henske, 2006; Curatolo, Bombardieri & Jozwiak, 2008). Pathological manifestations in these organ systems often include tumor growths or tissue malformations (hamartomas). While penetrance is high, expressivity of TSC phenotypes is highly variable. The birth incidence of TSC is approximately 1:6,000 (Osborne, Fryer, & Webb, 1991). This chapter is an updated and extended version of a previous article on this topic (Ehninger, de Vries, & Silva, 2009)

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Fifteen-minute consultation: Monogenic forms of diabetes with onset after age 6 months

Archives of Disease in Childhood - Education and Practice ◽

10.1136/archdischild-2016-311470 ◽

2017 ◽

Vol 103 (2) ◽

pp. 58-64

Author(s):

Emma M Dyer ◽

Rakesh Amin

Keyword(s):

Beta Cell Function ◽

Autosomal Dominant ◽

Cell Function ◽

Single Gene ◽

Pancreatic Beta Cell ◽

Gene Mutations ◽

Autosomal Dominant Fashion ◽

Monogenic Forms Of Diabetes ◽

Pancreatic Beta Cell Function

Monogenic forms of diabetes (historically known as Maturity Onset Diabetes of the Young (MODY)) are caused by single gene mutations inherited in an autosomal dominant fashion that result in reduced pancreatic beta cell function. Children with these forms of diabetes may be misdiagnosed as having type 1 or 2 diabetes, which has important implications for treatment, genetic counselling, screening of family members and prognosis. Useful tools now exist to aid in their diagnosis and management. Here, we attempt to outline the clinical features that will help the physician make the differentiation from other diabetes subtypes.

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Inflammation-Related Carcinogenesis: Lessons from Animal Models to Clinical Aspects

Cancers ◽

10.3390/cancers13040921 ◽

2021 ◽

Vol 13 (4) ◽

pp. 921

Author(s):

Futoshi Okada ◽

Runa Izutsu ◽

Keisuke Goto ◽

Mitsuhiko Osaki

Keyword(s):

Animal Models ◽

Tissue Injury ◽

Economic Status ◽

Gene Mutations ◽

Inflammatory Cells ◽

The Body ◽

Clinical Aspects ◽

Promote Cell Proliferation ◽

Organ Specific ◽

Altered Gene

Inflammation-related carcinogenesis has long been known as one of the carcinogenesis patterns in humans. Common carcinogenic factors are inflammation caused by infection with pathogens or the uptake of foreign substances from the environment into the body. Inflammation-related carcinogenesis as a cause for cancer-related death worldwide accounts for approximately 20%, and the incidence varies widely by continent, country, and even region of the country and can be affected by economic status or development. Many novel approaches are currently available concerning the development of animal models to elucidate inflammation-related carcinogenesis. By learning from the oldest to the latest animal models for each organ, we sought to uncover the essential common causes of inflammation-related carcinogenesis. This review confirmed that a common etiology of organ-specific animal models that mimic human inflammation-related carcinogenesis is prolonged exudation of inflammatory cells. Genotoxicity or epigenetic modifications by inflammatory cells resulted in gene mutations or altered gene expression, respectively. Inflammatory cytokines/growth factors released from inflammatory cells promote cell proliferation and repair tissue injury, and inflammation serves as a “carcinogenic niche”, because these fundamental biological events are common to all types of carcinogenesis, not just inflammation-related carcinogenesis. Since clinical strategies are needed to prevent carcinogenesis, we propose the therapeutic apheresis of inflammatory cells as a means of eliminating fundamental cause of inflammation-related carcinogenesis.

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A Case Report of a Prenatally Missed Mowat-Wilson Syndrome With Isolated Corpus Callosum Agenesis

Child Neurology Open ◽

10.1177/2329048x211006511 ◽

2021 ◽

Vol 8 ◽

pp. 2329048X2110065

Author(s):

Nesrin Şenbil ◽

Zeynep Arslan ◽

Derya Beyza Sayın Kocakap ◽

Yasemin Bilgili

Keyword(s):

Corpus Callosum ◽

Autosomal Dominant ◽

Genetic Disorder ◽

Gene Mutations ◽

Hirschsprung Disease ◽

Agenesis Of Corpus Callosum ◽

Whole Exome ◽

Congenital Cardiac Anomalies ◽

History Of ◽

Gene Mutation Analysis

Mowat–Wilson syndrome (MWS) is an autosomal dominant genetic disorder caused by ZEB2 gene mutations, manifesting with unique facial characteristics, moderate to severe intellectual problems, and congenital malformations as Hirschsprung disease, genital and ophthalmological anomalies, and congenital cardiac anomalies. Herein, a case of 1-year-old boy with isolated agenesis of corpus callosum (IACC) in the prenatal period is presented. He was admitted postnatally with Hirschsprung disease (HSCR), hypertelorism, uplifted earlobes, deeply set eyes, frontal bossing, oval-shaped nasal tip, ‘‘M’’ shaped upper lip, opened mouth and prominent chin, and developmental delay. Hence, MWS was primarily considered and confirmed by the ZEB2 gene mutation analysis. His karyotype was normal. He had a history of having a prenatally terminated brother with similar features. Antenatally detected IACC should prompt a detailed investigation including karyotype and microarray; even if they are normal then whole exome sequencing (WES) should be done.

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Mirtron-mediated RNA knockdown/replacement therapy for the treatment of dominant retinitis pigmentosa

Nature Communications ◽

10.1038/s41467-021-25204-3 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Harry O. Orlans ◽

Michelle E. McClements ◽

Alun R. Barnard ◽

Cristina Martinez-Fernandez de la Camara ◽

Robert E. MacLaren

Keyword(s):

Retinitis Pigmentosa ◽

Autosomal Dominant ◽

Gene Mutations ◽

Adeno Associated Virus ◽

Treatment Development ◽

Common Cause ◽

Toxic Protein ◽

Rna Knockdown

AbstractRhodopsin (RHO) gene mutations are a common cause of autosomal dominant retinitis pigmentosa (ADRP). The need to suppress toxic protein expression together with mutational heterogeneity pose challenges for treatment development. Mirtrons are atypical RNA interference effectors that are spliced from transcripts as short introns. Here, we develop a novel mirtron-based knockdown/replacement gene therapy for the mutation-independent treatment of RHO-related ADRP, and demonstrate efficacy in a relevant mammalian model. Splicing and potency of rhodopsin-targeting candidate mirtrons are initially determined, and a mirtron-resistant codon-modified version of the rhodopsin coding sequence is validated in vitro. These elements are then combined within a single adeno-associated virus (AAV) and delivered subretinally in a RhoP23H knock-in mouse model of ADRP. This results in significant mouse-to-human rhodopsin RNA replacement and is associated with a slowing of retinal degeneration. This provides proof of principle that synthetic mirtrons delivered by AAV are capable of reducing disease severity in vivo.

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Metabolic disturbances of the vitamin A pathway in human diaphragmatic hernia

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00108.2014 ◽

2015 ◽

Vol 308 (2) ◽

pp. L147-L157 ◽

Cited By ~ 15

Author(s):

Karen Coste ◽

Leonardus W. J. E. Beurskens ◽

Pierre Blanc ◽

Denis Gallot ◽

Amélie Delabaere ◽

...

Keyword(s):

Diaphragmatic Hernia ◽

Perinatal Death ◽

Single Gene ◽

Gene Mutations ◽

Transcriptional Analysis ◽

Metabolic Disturbances ◽

Common Life ◽

Retinoid Signaling ◽

Life Threatening ◽

Surgically Induced

Congenital diaphragmatic hernia (CDH) is a common life-threatening congenital anomaly resulting in high rates of perinatal death and neonatal respiratory distress. Some of the nonisolated forms are related to single-gene mutations or genomic rearrangements, but the genetics of the isolated forms (60% of cases) still remains a challenging issue. Retinoid signaling (RA) is critical for both diaphragm and lung development, and it has been hypothesized that subtle disruptions of this pathway could contribute to isolated CDH etiology. Here we used time series of normal and CDH lungs in humans, in nitrofen-exposed rats, and in surgically induced hernia in rabbits to perform a systematic transcriptional analysis of the RA pathway key components. The results point to CRPBP2, CY26B1, and ALDH1A2 as deregulated RA signaling genes in human CDH. Furthermore, the expression profile comparisons suggest that ALDH1A2 overexpression is not a primary event, but rather a consequence of the CDH-induced lung injury. Taken together, these data show that RA signaling disruption is part of CDH pathogenesis, and also that dysregulation of this pathway should be considered organ specifically.

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Single gene mutations in early embryonic loss

Journal of Assisted Reproduction and Genetics ◽

10.1007/bf01204244 ◽

1992 ◽

Vol 9 (6) ◽

pp. 504-505 ◽

Cited By ~ 2

Author(s):

Yury Verlinsky

Keyword(s):

Single Gene ◽

Gene Mutations ◽

Embryonic Loss

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Measuring learning in individual flies is not necessary to study the effects of single-gene mutations inDrosophila: A reply to Holliday and Hirsch

Behavior Genetics ◽

10.1007/bf01074264 ◽

1986 ◽

Vol 16 (4) ◽

pp. 449-455 ◽

Cited By ~ 3

Author(s):

Tim Tully

Keyword(s):

Single Gene ◽

Gene Mutations

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Whole-exome sequencing associates novel CSMD1 gene mutations with familial Parkinson disease

Neurology Genetics ◽

10.1212/nxg.0000000000000177 ◽

2017 ◽

Vol 3 (5) ◽

pp. e177 ◽

Cited By ~ 12

Author(s):

Javier Ruiz-Martínez ◽

Luis J. Azcona ◽

Alberto Bergareche ◽

Jose F. Martí-Massó ◽

Coro Paisán-Ruiz

Keyword(s):

Parkinson Disease ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Genome Wide Association Study ◽

Single Gene ◽

Gene Mutations ◽

Complement Control Protein ◽

Genome Wide ◽

Whole Exome ◽

A Genome

Objective:Despite the enormous advancements made in deciphering the genetic architecture of Parkinson disease (PD), the majority of PD is idiopathic, with single gene mutations explaining only a small proportion of the cases.Methods:In this study, we clinically evaluated 2 unrelated Spanish families diagnosed with PD, in which known PD genes were previously excluded, and performed whole-exome sequencing analyses in affected individuals for disease gene identification.Results:Patients were diagnosed with typical PD without relevant distinctive symptoms. Two different novel mutations were identified in the CSMD1 gene. The CSMD1 gene, which encodes a complement control protein that is known to participate in the complement activation and inflammation in the developing CNS, was previously shown to be associated with the risk of PD in a genome-wide association study.Conclusions:We conclude that the CSMD1 mutations identified in this study might be responsible for the PD phenotype observed in our examined patients. This, along with previous reported studies, may suggest the complement pathway as an important therapeutic target for PD and other neurodegenerative diseases.

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