scholarly journals Non-Penetrance for Ocular Phenotype in Two Individuals Carrying Heterozygous Loss-of-Function ZEB1 Alleles

Genes ◽  
2021 ◽  
Vol 12 (5) ◽  
pp. 677
Author(s):  
Lubica Dudakova ◽  
Viktor Stranecky ◽  
Lenka Piherova ◽  
Tomas Palecek ◽  
Nikolas Pontikos ◽  
...  
Keyword(s):  
General Population ◽  
Autosomal Dominant ◽  
Low Frequency ◽  
Corneal Dystrophy ◽  
Loss Of Function ◽  
Autosomal Dominant Disorder ◽  
Extremely Low Frequency ◽  
Posterior Polymorphous Corneal Dystrophy ◽  
Type 3

ZEB1 loss-of-function (LoF) alleles are known to cause a rare autosomal dominant disorder—posterior polymorphous corneal dystrophy type 3 (PPCD3). To date, 50 pathogenic LoF variants have been identified as disease-causing and familial studies have indicated that the PPCD3 phenotype is penetrant in approximately 95% of carriers. In this study, we interrogated in-house exomes (n = 3616) and genomes (n = 88) for the presence of putative heterozygous LoF variants in ZEB1. Next, we performed detailed phenotyping in a father and his son who carried a novel LoF c.1279C>T; p.(Glu427*) variant in ZEB1 (NM_030751.6) absent from the gnomAD v.2.1.1 dataset. Ocular examination of the two subjects did not show any abnormalities characteristic of PPCD3. GnomAD (n = 141,456 subjects) was also interrogated for LoF ZEB1 variants, notably 8 distinct heterozygous changes presumed to lead to ZEB1 haploinsufficiency, not reported to be associated with PPCD3, have been identified. The NM_030751.6 transcript has a pLI score ≥ 0.99, indicating extreme intolerance to haploinsufficiency. In conclusion, ZEB1 LoF variants are present in a general population at an extremely low frequency. As PPCD3 can be asymptomatic, the true penetrance of ZEB1 LoF variants remains currently unknown but is likely to be lower than estimated by the familial led approaches adopted to date.

scholarly journals Heterozygous deletions at the ZEB1 locus verify haploinsufficiency as the mechanism of disease for posterior polymorphous corneal dystrophy type 3

2015 ◽  
Vol 24 (7) ◽  
pp. 985-991 ◽  
Author(s):  
Petra Liskova ◽  
Cerys J Evans ◽  
Alice E Davidson ◽  
Marketa Zaliova ◽  
Lubica Dudakova ◽  
...  
Keyword(s):  
Corneal Dystrophy ◽  
Posterior Polymorphous Corneal Dystrophy ◽  
Type 3

Caution in interpretation of disease causality for heterozygous loss-of-function variants in the MYH8 gene associated with autosomal dominant disorder

2017 ◽  
Vol 60 (6) ◽  
pp. 312-316 ◽  
Author(s):  
Zunyan Dai ◽  
Zachary Whitt ◽  
Lindsey C. Mighion ◽  
Alessandro Pontoglio ◽  
Lora J.H. Bean ◽  
...  
Keyword(s):  
Autosomal Dominant ◽  
Loss Of Function ◽  
Autosomal Dominant Disorder ◽  
Disease Causality

scholarly journals Coincidental Occurrence of Schnyder Corneal Dystrophy and Posterior Polymorphous Corneal Dystrophy Type 3

Cornea ◽  
2019 ◽  
Vol 38 (6) ◽  
pp. 758-760
Author(s):  
Lubica Dudakova ◽  
Pavlina Skalicka ◽  
Alice E. Davidson ◽  
Petra Liskova
Keyword(s):  
Corneal Dystrophy ◽  
Posterior Polymorphous Corneal Dystrophy ◽  
Schnyder Corneal Dystrophy ◽  
Type 3

scholarly journals A de novo STUB1 variant associated with an early adult-onset multisystemic ataxia phenotype

2021 ◽  
Author(s):  
David Mengel ◽  
Andreas Traschütz ◽  
Selina Reich ◽  
Alejandra Leyva-Gutiérrez ◽  
Friedemann Bender ◽  
...  
Keyword(s):  
Early Onset ◽  
Autosomal Recessive ◽  
Autosomal Dominant ◽  
De Novo ◽  
Family Members ◽  
Start Codon ◽  
Mrna Levels ◽  
Adult Onset ◽  
Loss Of Function ◽  
Autosomal Dominant Disorder

Abstract Background Biallelic STUB1 variants are a well-established cause of autosomal-recessive early-onset multisystemic ataxia (SCAR16). Evidence for STUB1 variants causing autosomal-dominant ataxia (SCA48) so far largely relies on segregation data in larger families. Presenting the first de novo occurrence of a heterozygous STUB1 variant, we here present additional qualitative evidence for STUB1-disease as an autosomal-dominant disorder. Methods Whole exome sequencing on an index patient with sporadic early-onset ataxia, followed by Sanger sequencing in all family members, was used to identify causative variants as well as to rule out alternative genetic hits and intronic STUB1 variants. STUB1 mRNA and protein levels in PBMCs in all family members were analysed using qRT-PCR and Western Blot. Results A previously unreported start-lost loss-of-function variant c.3G>A in the start codon of STUB1 was identified in the index case, occurring de novo and without evidence for a second (potentially missed) variant (e.g., intronic or copy number) in STUB1. The patient showed an early adult-onset multisystemic ataxia complicated by spastic gait disorder, distal myoclonus and cognitive dysfunction, thus closely mirroring the systems affected in autosomal-recessive STUB1-associated disease. In line with the predicted start-lost effect of the variant, functional investigations demonstrated markedly reduced STUB1 protein expression in PBMCs, whereas mRNA levels were intact. Conclusion De novo occurrence of the loss-of-function STUB1 variant in our case with multisystemic ataxia provides a qualitatively additional line of evidence for STUB1-disease as an autosomal-dominant disorder, in which the same neurological systems are affected as in its autosomal-recessive counterpart. Moreover, this finding adds support for loss-of-function as a mechanism underlying autosomal-dominant STUB1-disease, thus mirroring its autosomal-recessive counterpart also in terms of the underlying mutational mechanism.

The utility of massively parallel sequencing for posterior polymorphous corneal dystrophy type 3 molecular diagnosis

2019 ◽  
Vol 182 ◽  
pp. 160-166 ◽  
Author(s):  
Lubica Dudakova ◽  
Cerys J. Evans ◽  
Nikolas Pontikos ◽  
Nathaniel J. Hafford-Tear ◽  
Frantisek Malinka ◽  
...  
Keyword(s):  
Molecular Diagnosis ◽  
Massively Parallel Sequencing ◽  
Corneal Dystrophy ◽  
Massively Parallel ◽  
Parallel Sequencing ◽  
Posterior Polymorphous Corneal Dystrophy ◽  
Type 3

scholarly journals Schnyder corneal dystrophy-associated UBIAD1 is defective in MK-4 synthesis and resists autophagy-mediated degradation

2020 ◽  
Vol 61 (5) ◽  
pp. 746-757
Author(s):  
Dong-Jae Jun ◽  
Marc M. Schumacher ◽  
Seonghwan Hwang ◽  
Lisa N. Kinch ◽  
Nick V. Grishin ◽  
...  
Keyword(s):  
Autosomal Dominant ◽  
Corneal Dystrophy ◽  
Inhibitory Effect ◽  
Synthetic Activity ◽  
Autosomal Dominant Disorder ◽  
Intact Cells ◽  
Rate Limiting Step ◽  
Coa Reductase ◽  
Schnyder Corneal Dystrophy ◽  
Rate Limiting

The autosomal dominant disorder Schnyder corneal dystrophy (SCD) is caused by mutations in UbiA prenyltransferase domain-containing protein-1 (UBIAD1), which uses geranylgeranyl pyrophosphate (GGpp) to synthesize the vitamin K2 subtype menaquinone-4 (MK-4). SCD is characterized by opacification of the cornea, owing to aberrant build-up of cholesterol in the tissue. We previously discovered that sterols stimulate association of UBIAD1 with ER-localized HMG-CoA reductase, which catalyzes a rate-limiting step in the synthesis of cholesterol and nonsterol isoprenoids, including GGpp. Binding to UBIAD1 inhibits sterol-accelerated ER-associated degradation (ERAD) of reductase and permits continued synthesis of GGpp in cholesterol-replete cells. GGpp disrupts UBIAD1-reductase binding and thereby allows for maximal ERAD of reductase as well as ER-to-Golgi translocation of UBIAD1. SCD-associated UBIAD1 is refractory to GGpp-mediated dissociation from reductase and remains sequestered in the ER to inhibit ERAD. Here, we report development of a biochemical assay for UBIAD1-mediated synthesis of MK-4 in isolated membranes and intact cells. Using this assay, we compared enzymatic activity of WT UBIAD1 with that of SCD-associated variants. Our studies revealed that SCD-associated UBIAD1 exhibited reduced MK-4 synthetic activity, which may result from its reduced affinity for GGpp. Sequestration in the ER protects SCD-associated UBIAD1 from autophagy and allows intracellular accumulation of the mutant protein, which amplifies the inhibitory effect on reductase ERAD. These findings have important implications not only for the understanding of SCD etiology but also for the efficacy of cholesterol-lowering statin therapy, which becomes limited, in part, because of UBIAD1-mediated inhibition of reductase ERAD.

PTEN-Related Overgrowth Syndromes

2019 ◽  
pp. 163-186
Author(s):  
Lamis Yehia ◽  
Joanne Ngeow ◽  
Charis Eng
Keyword(s):  
Autosomal Dominant ◽  
Vascular Malformations ◽  
Treatment Strategies ◽  
Suppressor Gene ◽  
Cowden Syndrome ◽  
Loss Of Function ◽  
Autosomal Dominant Disorder ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Cell Growth And Proliferation

Individuals carrying germline mutations in the tumor suppressor gene phosphatase and tensin homolog (PTEN) may present with diverse clinical phenotypes, grouped under the term of PTEN hamartoma tumor syndrome (PHTS). This chapter will focus on two PHTS conditions: Bannayan-Riley-Ruvalcaba syndrome and Cowden syndrome. The first condition is an autosomal dominant disorder characterized by macrocephaly, intestinal hamartomatous polyposis, vascular malformations, lipomas, hemangiomas, and genital freckling. Other features include developmental delay, hypotonia, and scoliosis. Cowden syndrome is also an autosomal dominant disorder, mainly characterized by multiple hamartomas and high risk of breast, thyroid, and other cancers. PTEN encodes the main inhibitor of the PI3K-AKT pathway, regulating cell growth and proliferation, and protein synthesis. Therefore, germline loss-of-function mutations in this gene lead to excessive growth, particularly affecting connective tissues. Detection of PTEN mutations is critical for clinical management and treatment strategies.

Nail-Patella Syndrome

2015 ◽  
Vol 19 (6) ◽  
pp. 595-599 ◽  
Author(s):  
Najla Al-Dawsari ◽  
Ahmed Al-Mokhadam ◽  
Hind Al-Abdulwahed ◽  
Nouriya Al-Sannaa
Keyword(s):  
Autosomal Recessive ◽  
Autosomal Dominant ◽  
Anterior Segment ◽  
Heterozygous Mutation ◽  
Loss Of Function ◽  
Consanguineous Family ◽  
Autosomal Dominant Disorder ◽  
Nail Changes ◽  
Chromosome 9Q ◽  
Nail Patella Syndrome

Background: Nail-patella syndrome (NPS) is an autosomal dominant disorder with a variable interfamilial and intrafamilial clinical expressivity and penetrance. It is caused by loss-of-function heterozygous mutation in the LIM-homeodomain transcription factor (LMX1B) located on chromosome 9q. The pleiotropic LMB1X gene, a member of the homeogene family, is involved in the development of glomerular basement membrane, dorsoventral limb structures, along with the nails and the anterior segment of the eye. Objective: Here, we report a Saudi Arab consanguineous family with 2 affected sisters presented with the typical nail changes of NPS. Methods: DNA samples were collected from the sisters and their parents after consent. Results: Both sisters were found to be homozygous for a previously described disease-causing mutation (c.268C>T) at the (LMX1B) gene. Both of the phenotypically normal parents were confirmed to be heterozygous for the same mutation. Conclusion: This finding supports the autosomal recessive mode of inheritance in this family.

scholarly journals The prenyltransferase UBIAD1 is the target of geranylgeraniol in degradation of HMG CoA reductase

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Marc M Schumacher ◽  
Rania Elsabrouty ◽  
Joachim Seemann ◽  
Youngah Jo ◽  
Russell A DeBose-Boyd
Keyword(s):  
Autosomal Dominant ◽  
Corneal Dystrophy ◽  
Vitamin K2 ◽  
Biosynthetic Enzyme ◽  
Autosomal Dominant Disorder ◽  
Gene Encoding ◽  
Hmg Coa Reductase ◽  
Abnormal Accumulation ◽  
Coa Reductase ◽  
Schnyder Corneal Dystrophy

Schnyder corneal dystrophy (SCD) is an autosomal dominant disorder in humans characterized by abnormal accumulation of cholesterol in the cornea. SCD-associated mutations have been identified in the gene encoding UBIAD1, a prenyltransferase that synthesizes vitamin K2. Here, we show that sterols stimulate binding of UBIAD1 to the cholesterol biosynthetic enzyme HMG CoA reductase, which is subject to sterol-accelerated, endoplasmic reticulum (ER)-associated degradation augmented by the nonsterol isoprenoid geranylgeraniol through an unknown mechanism. Geranylgeraniol inhibits binding of UBIAD1 to reductase, allowing its degradation and promoting transport of UBIAD1 from the ER to the Golgi. CRISPR-CAS9-mediated knockout of UBIAD1 relieves the geranylgeraniol requirement for reductase degradation. SCD-associated mutations in UBIAD1 block its displacement from reductase in the presence of geranylgeraniol, thereby preventing degradation of reductase. The current results identify UBIAD1 as the elusive target of geranylgeraniol in reductase degradation, the inhibition of which may contribute to accumulation of cholesterol in SCD.

scholarly journals Nail-Patella Syndrome

2000 ◽  
Vol 11 (9) ◽  
pp. 1762-1766 ◽  
Author(s):  
NINE V.A.M. KNOERS ◽  
ERNIE M.H.F. BONGERS ◽  
SYLVIA E.C. VAN BEERSUM ◽  
ED J.P. LOMMEN ◽  
HANS VAN BOKHOVEN ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Renal Impairment ◽  
Renal Disease ◽  
Autosomal Dominant ◽  
Family Members ◽  
Loss Of Function ◽  
Autosomal Dominant Disorder ◽  
High Incidence ◽  
Novel Variant ◽  
Nail Patella Syndrome

Abstract. Nail-patella syndrome is an autosomal dominant disorder characterized by dyplasia of finger nails, skeletal anomalies, and, frequently, renal disease. It has recently been shown that this disorder is caused by putative loss-of-function mutations in a transcription factor (LMX1B) belonging to the LIM-homeodomain family, members of which are known to be important for pattern formation during development. A cohort of eight Dutch NPS families were screened for mutations in the LMX1B gene; seven different mutations, including one novel variant, were identified. Three of the mutations are very likely to result in truncated LMX1B proteins, three are predicted to influence sequence-specific DNA binding, and one is presumed to prevent the formation of a stable protein by abolishing the Zn(II) binding site of the protein. Although there was a remarkable high incidence of renal disease in one of the families, the nephropathy was not seen in all affected family members and the severity of renal impairment varied significantly among the patients. This indicates that the incidence and severity of nephropathy within this family cannot be attributed to the LMX1B genotype. In addition, evidence of a correlation between other characteristics of the NPS phenotype and specific mutations has not been found.

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