Search

Your search keyword '"Schneeberger PE"' showing total 2 results
Start Over Author "Schneeberger PE" Topic craniofacial abnormalities
2 results on '"Schneeberger PE"'

1. Roberts syndrome in an Indian patient with humeroradial synostosis, congenital elbow contractures and a novel homozygous splice variant in ESCO2.

Author

Schneeberger PE, Nayak SS, Fuchs S, Kutsche K, and Girisha KM

Subjects
Child, Preschool, Contracture complications, Contracture genetics, Contracture pathology, Craniofacial Abnormalities complications, Craniofacial Abnormalities genetics, Ectromelia complications, Ectromelia genetics, Homozygote, Humans, Humerus pathology, Hypertelorism complications, Hypertelorism genetics, Male, Phenotype, Radius pathology, Synostosis complications, Synostosis genetics, Acetyltransferases genetics, Chromosomal Proteins, Non-Histone genetics, Contracture congenital, Craniofacial Abnormalities pathology, Ectromelia pathology, Elbow pathology, Humerus abnormalities, Hypertelorism pathology, Mutation, RNA Splicing, Radius abnormalities, Synostosis pathology
Abstract

Roberts syndrome (also known as Roberts-SC phocomelia syndrome) is an autosomal recessive developmental disorder, characterized by pre- and postnatal growth retardation, limb malformations including bilateral symmetric tetraphocomelia or mesomelia, and craniofacial dysmorphism. Biallelic loss-of-function variants in ESCO2, which codes for establishment of sister chromatid cohesion N-acetyltransferase 2, cause Roberts syndrome. Phenotypic spectrum among patients is broad, challenging clinical diagnosis in mildly affected individuals. Here we report a 3-year-old boy with a mild phenotype of Roberts syndrome with bilateral elbow contractures, humeroradial synostosis, mild lower limb disparity, and facial dysmorphism. Trio whole-exome sequencing identified the novel biallelic splice variant c.1673+1G>A in ESCO2 in the patient. Aberrant ESCO2 pre-mRNA splicing, reduced relative ESCO2 mRNA amount, and characteristic cytogenetic defects, such as premature centromere separation, heterochromatin repulsion, and chromosome breaks, in patient cells strongly supported pathogenicity of the ESCO2 variant affecting one of the highly conserved guanine-thymine dinucleotide of the donor splice site. Our case highlights the difficulty in establishing a clinical diagnosis in individuals with minor clinical features of Roberts syndrome and normal intellectual and social development. However, next-generation sequencing tools allow for molecular diagnosis in cases presenting with mild developmental defects., (© 2020 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Published
2020
Full Text
View/download PDF

2. Gain-of-Function Mutations in KCNN3 Encoding the Small-Conductance Ca 2+ -Activated K + Channel SK3 Cause Zimmermann-Laband Syndrome.

Author

Bauer CK, Schneeberger PE, Kortüm F, Altmüller J, Santos-Simarro F, Baker L, Keller-Ramey J, White SM, Campeau PM, Gripp KW, and Kutsche K

Subjects
Abnormalities, Multiple pathology, Adult, Amino Acid Sequence, Animals, CHO Cells, Child, Child, Preschool, Craniofacial Abnormalities pathology, Cricetinae, Cricetulus, Female, Fibromatosis, Gingival pathology, Hand Deformities, Congenital pathology, Humans, Ion Channel Gating, Male, Middle Aged, Phenotype, Protein Conformation, Sequence Homology, Small-Conductance Calcium-Activated Potassium Channels chemistry, Small-Conductance Calcium-Activated Potassium Channels metabolism, Abnormalities, Multiple etiology, Craniofacial Abnormalities etiology, Fibromatosis, Gingival etiology, Gain of Function Mutation, Hand Deformities, Congenital etiology, Small-Conductance Calcium-Activated Potassium Channels genetics
Abstract

Zimmermann-Laband syndrome (ZLS) is characterized by coarse facial features with gingival enlargement, intellectual disability (ID), hypertrichosis, and hypoplasia or aplasia of nails and terminal phalanges. De novo missense mutations in KCNH1 and KCNK4, encoding K + channels, have been identified in subjects with ZLS and ZLS-like phenotype, respectively. We report de novo missense variants in KCNN3 in three individuals with typical clinical features of ZLS. KCNN3 (SK3/KCa2.3) constitutes one of three members of the small-conductance Ca 2+ -activated K + (SK) channels that are part of a multiprotein complex consisting of the pore-forming channel subunits, the constitutively bound Ca 2+ sensor calmodulin, protein kinase CK2, and protein phosphatase 2A. CK2 modulates Ca 2+ sensitivity of the channels by phosphorylating SK-bound calmodulin. Patch-clamp whole-cell recordings of KCNN3 channel-expressing CHO cells demonstrated that disease-associated mutations result in gain of function of the mutant channels, characterized by increased Ca 2+ sensitivity leading to faster and more complete activation of KCNN3 mutant channels. Pretreatment of cells with the CK2 inhibitor 4,5,6,7-tetrabromobenzotriazole revealed basal inhibition of wild-type and mutant KCNN3 channels by CK2. Analogous experiments with the KCNN3 p.Val450Leu mutant previously identified in a family with portal hypertension indicated basal constitutive channel activity and thus a different gain-of-function mechanism compared to the ZLS-associated mutant channels. With the report on de novo KCNK4 mutations in subjects with facial dysmorphism, hypertrichosis, epilepsy, ID, and gingival overgrowth, we propose to combine the phenotypes caused by mutations in KCNH1, KCNK4, and KCNN3 in a group of neurological potassium channelopathies caused by an increase in K + conductance., (Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Published
2019
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results