scholarly journals Loss-of-Function Mutations in the LIM-Homeodomain Gene, LMX1B, in Nail-Patella Syndrome

1998 ◽  
Vol 7 (7) ◽  
pp. 1091-1098 ◽  
Author(s):  
D. Vollrath ◽  
V. L. Jaramillo-Babb ◽  
M. V. Clough ◽  
I. McIntosh ◽  
K. M. Scott ◽  
...  
Keyword(s):  
Loss Of Function ◽  
Nail Patella Syndrome ◽  
Lim Homeodomain

scholarly journals Identification of limb-specific Lmx1b auto-regulatory modules with Nail-Patella Syndrome pathogenicity

2020 ◽  
Author(s):  
Endika Haro ◽  
Florence Petit ◽  
Charmaine U. Pira ◽  
Conor D. Spady ◽  
Lauren A. Ivey ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Cerebellar Development ◽  
Loss Of Function ◽  
Disease Pathogenesis ◽  
Functional Allele ◽  
Regulatory Modules ◽  
Patient Families ◽  
Nail Dysplasia ◽  
Nail Patella Syndrome

AbstractLMX1B haploinsufficiency causes Nail-patella syndrome (NPS; MIM 161200), characterized by nail dysplasia, absent/hypoplastic patellae, chronic kidney disease, and glaucoma. Accordingly, in mice Lmx1b has been shown to play crucial roles in the development of the limb, kidney and eye. Although one functional allele of murine Lmx1b appears adequate for development, Lmx1b null mice display ventral-ventral distal limbs with abnormal kidney, eye and cerebellar development, more disruptive, but fully concordant with NPS. Interestingly, in Lmx1b functional knockouts (KOs), Lmx1b transcription in the limb is decreased nearly 6-fold indicating autoregulation. Herein, we report on two conserved Lmx1b-associated cis-regulatory modules (LARM1 and LARM2) that are bound by Lmx1b, amplify Lmx1b expression in the limb and are necessary for Lmx1b-mediated limb dorsalization. Remarkably, we also report on two NPS patient families with normal LMX1B coding sequence, but loss-of-function variations in the LARM1/2 region, stressing the role of regulatory modules in disease pathogenesis.

Internal Carotid Artery Aplasia in a Patient With Nail-Patella Syndrome

2019 ◽  
Vol 54 (2) ◽  
pp. 175-181
Author(s):  
Jacqueline Kraus ◽  
Muhammad Umair Jahngir ◽  
Baljinder Singh ◽  
Adnan I. Qureshi
Keyword(s):  
Carotid Artery ◽  
Internal Carotid Artery ◽  
Protein Function ◽  
Internal Carotid ◽  
Homeobox Gene ◽  
Limb Bud ◽  
Abnormal Development ◽  
Loss Of Function ◽  
Congenital Aplasia ◽  
Nail Patella Syndrome

Nail-patella syndrome (NPS) is a rare disorder characterized by abnormal development of ectodermal and mesodermal tissues. Classically, NPS presents as a triad of nail dysplasia, dysplastic patellae, and bony exostoses of the ilia known as “iliac horns.” Apart from dermatological and skeletal abnormalities, patients may also have involvement of ophthalmologic and renal systems. The underlying molecular etiology in NPS is the mutation of LMX1B homeobox gene which results in loss of function of its protein also called LMX1B, a DNA-binding protein belonging to the larger LIM-homeodomain transcription factor family. Normal LMX1B gene and protein function are essential for dorsalization of the vertebrate limb bud, development of anterior eye structures, skull formation, and differentiation and migration of neurons in the central nervous system. We report a case of confirmed NPS presenting with congenital aplasia of the internal carotid artery and believe this is the first report of cerebrovascular developmental abnormality associated with NPS.

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 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.

scholarly journals Identification of limb-specific Lmx1b auto-regulatory modules with Nail-patella syndrome pathogenicity

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Endika Haro ◽  
Florence Petit ◽  
Charmaine U. Pira ◽  
Conor D. Spady ◽  
Sara Lucas-Toca ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Cerebellar Development ◽  
Loss Of Function ◽  
Disease Pathogenesis ◽  
Functional Allele ◽  
Regulatory Modules ◽  
Patient Families ◽  
Nail Dysplasia ◽  
Nail Patella Syndrome

AbstractLMX1B haploinsufficiency causes Nail-patella syndrome (NPS; MIM 161200), characterized by nail dysplasia, absent/hypoplastic patellae, chronic kidney disease, and glaucoma. Accordingly in mice, Lmx1b has been shown to play crucial roles in the development of the limb, kidney and eye. Although one functional allele of Lmx1b appears adequate for development, Lmx1b null mice display ventral-ventral distal limbs with abnormal kidney, eye and cerebellar development, more disruptive, but fully concordant with NPS. In Lmx1b functional knockouts (KOs), Lmx1b transcription in the limb is decreased nearly 6-fold, indicating autoregulation. Herein, we report on two conserved Lmx1b-associated cis-regulatory modules (LARM1 and LARM2) that are bound by Lmx1b, amplify Lmx1b expression with unique spatial modularity in the limb, and are necessary for Lmx1b-mediated limb dorsalization. These enhancers, being conserved across vertebrates (including coelacanth, but not other fish species), and required for normal locomotion, provide a unique opportunity to study the role of dorsalization in the fin to limb transition. We also report on two NPS patient families with normal LMX1B coding sequence, but with loss-of-function variations in the LARM1/2 region, stressing the role of regulatory modules in disease pathogenesis.

scholarly journals Chip is an essential cofactor for apterous in the regulation of axon guidance in Drosophila

Development ◽  
2000 ◽  
Vol 127 (9) ◽  
pp. 1823-1831 ◽  
Author(s):  
D.J. van Meyel ◽  
D.D. O'Keefe ◽  
S. Thor ◽  
L.W. Jurata ◽  
G.N. Gill ◽  
...  
Keyword(s):  
Axon Guidance ◽  
Functional Unit ◽  
Loss Of Function ◽  
Homeodomain Proteins ◽  
Interaction Domain ◽  
Drosophila Wing ◽  
Embryonic Nervous System ◽  
Tetrameric Complex ◽  
Lim Homeodomain

LIM-homeodomain transcription factors are expressed in subsets of neurons and are required for correct axon guidance and neurotransmitter identity. The LIM-homeodomain family member Apterous requires the LIM-binding protein Chip to execute patterned outgrowth of the Drosophila wing. To determine whether Chip is a general cofactor for diverse LIM-homeodomain functions in vivo, we studied its role in the embryonic nervous system. Loss-of-function Chip mutations cause defects in neurotransmitter production that mimic apterous and islet mutants. Chip is also required cell-autonomously by Apterous-expressing neurons for proper axon guidance, and requires both a homodimerization domain and a LIM interaction domain to function appropriately. Using a Chip/Apterous chimeric molecule lacking domains normally required for their interaction, we reconstituted the complex and rescued the axon guidance defects of apterous mutants, of Chip mutants and of embryos doubly mutant for both apterous and Chip. Our results indicate that Chip participates in a range of developmental programs controlled by LIM-homeodomain proteins and that a tetrameric complex comprising two Apterous molecules bridged by a Chip homodimer is the functional unit through which Apterous acts during neuronal differentiation.

E3 ubiquitin ligases

2005 ◽  
Vol 41 ◽  
pp. 15-30 ◽  
Author(s):  
Helen C. Ardley ◽  
Philip A. Robinson
Keyword(s):  
Protein Complexes ◽  
Loss Of Function ◽  
Direct Role ◽  
Cellular Processes ◽  
Substrate Protein ◽  
Protein Ubiquitination ◽  
C Terminus ◽  
Full Complement ◽  
Spatio Temporal ◽  
Eukaryotic Organisms

The selectivity of the ubiquitin–26 S proteasome system (UPS) for a particular substrate protein relies on the interaction between a ubiquitin-conjugating enzyme (E2, of which a cell contains relatively few) and a ubiquitin–protein ligase (E3, of which there are possibly hundreds). Post-translational modifications of the protein substrate, such as phosphorylation or hydroxylation, are often required prior to its selection. In this way, the precise spatio-temporal targeting and degradation of a given substrate can be achieved. The E3s are a large, diverse group of proteins, characterized by one of several defining motifs. These include a HECT (homologous to E6-associated protein C-terminus), RING (really interesting new gene) or U-box (a modified RING motif without the full complement of Zn2+-binding ligands) domain. Whereas HECT E3s have a direct role in catalysis during ubiquitination, RING and U-box E3s facilitate protein ubiquitination. These latter two E3 types act as adaptor-like molecules. They bring an E2 and a substrate into sufficiently close proximity to promote the substrate's ubiquitination. Although many RING-type E3s, such as MDM2 (murine double minute clone 2 oncoprotein) and c-Cbl, can apparently act alone, others are found as components of much larger multi-protein complexes, such as the anaphase-promoting complex. Taken together, these multifaceted properties and interactions enable E3s to provide a powerful, and specific, mechanism for protein clearance within all cells of eukaryotic organisms. The importance of E3s is highlighted by the number of normal cellular processes they regulate, and the number of diseases associated with their loss of function or inappropriate targeting.

Sign in / Sign up

Export Citation Format

Share Document