First direct evidence of involvement of a homozygous loss‐of‐function variant in the <i>EPS15L1</i> gene underlying split‐hand/split‐foot malformation

Umair, Muhammad; Ullah, Asmat; Abbas, Safdar; Ahmad, Farooq; Basit, Sulman

doi:10.1111/cge.13152

Cited by 20 publications

(19 citation statements)

References 24 publications

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“…However, there is also a recent report stating that high Eps15 expression levels correlate with a favorable clinical outcome of breast cancer [196]. Deletions in the Eps15R gene have been linked to split-hand/split-foot malformation (SHFM) [197,198], showing once more an important role for Eps15R during development.…”

Section: Involvement Of Eps15 and Eps15r In Human Diseasementioning

confidence: 99%

Endocytic Adaptor Proteins in Health and Disease: Lessons from Model Organisms and Human Mutations

Tehran

López-Hernández

Maritzen

2019

Cells

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Cells need to exchange material and information with their environment. This is largely achieved via cell-surface receptors which mediate processes ranging from nutrient uptake to signaling responses. Consequently, their surface levels have to be dynamically controlled. Endocytosis constitutes a powerful mechanism to regulate the surface proteome and to recycle vesicular transmembrane proteins that strand at the plasma membrane after exocytosis. For efficient internalization, the cargo proteins need to be linked to the endocytic machinery via adaptor proteins such as the heterotetrameric endocytic adaptor complex AP-2 and a variety of mostly monomeric endocytic adaptors. In line with the importance of endocytosis for nutrient uptake, cell signaling and neurotransmission, animal models and human mutations have revealed that defects in these adaptors are associated with several diseases ranging from metabolic disorders to encephalopathies. This review will discuss the physiological functions of the so far known adaptor proteins and will provide a comprehensive overview of their links to human diseases.

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Section: Involvement Of Eps15 and Eps15r In Human Diseasementioning

confidence: 99%

Endocytic Adaptor Proteins in Health and Disease: Lessons from Model Organisms and Human Mutations

Tehran

López-Hernández

Maritzen

2019

Cells

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“…DNA of three affected individual (V-2, V-7, V-13) was subjected to exome sequencing using Illumina HiSeq 2500 (Umair, Ullah, Abbas, et al, 2018). After WES, filters were applied for screening different variants.…”

Section: Wes and Sanger Sequencingmentioning

confidence: 99%

Exome sequencing revealed a novel loss‐of‐function variant in the GLI3 transcriptional activator 2 domain underlies nonsyndromic postaxial polydactyly

Umair

Wasif

Albalawi

et al. 2019

Molec Gen & Gen Med

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Background Polydactyly is a common genetic limb deformity characterized by the presence of extra fingers or toes. This anomaly may occur in isolation (nonsyndromic) or as part of a syndrome. The disease is broadly divided into preaxial polydactyly (PPD; duplication of thumb), mesoaxial polydactyly (complex polydactyly), and postaxial polydactyly (PAP: duplication of the fifth finger). The extra digits may be present in one or both the limbs. Heterozygous variants in the GLI3 , ZRS / SHH , and PITX1 have been associated with autosomal dominant polydactyly, while homozygous variants in the ZNF141 , IQCE , GLI1 , and FAM92A have been associated with autosomal recessive polydactyly. Pathogenic mutations in the GLI3 gene (glioma‐associated oncogene family zinc finger 3) have been associated with both nonsyndromic and syndromic polydactyly. Methods Here, we report an extended five generation kindred having 12 affected individuals exhibiting nonsyndromic postaxial polydactyly type A condition. Whole‐exome sequencing followed by variant prioritization, bioinformatic studies, Sanger validation, and segregation analysis was performed. Results Using exome sequencing in the three affected individuals, we identified a novel heterozygous frameshift variant (c.3567_3568insG; p.Ala1190Glyfs*57) in the transcriptional activator (TA2) domain of the GLI3 encoding gene. Conclusion To the best of our knowledge, the present study reports on the first familial case of nonsyndromic postaxial polydactyly due to the GLI3 variant in Pakistani population. Our study also demonstrated the important role of GLI3 in causing nonsyndromic postaxial polydactyly.

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“…Mutations in TP63 , DLX5 , DLX6 , FGFR1 , BHLHA9 , and WNT10B are known to be associated with SHFM in humans, and interestingly the clinical features of SHFM caused by mutations of these genes are not distinguishable . This implies that in a normal situation these SHFM‐associated genes share in part an underlying regulatory pathway that is involved in development of hands and feet (Figure ).…”

Section: Shfm‐associated Genesmentioning

confidence: 99%

Genetic regulatory pathways of split‐hand/foot malformation

Kantaputra

Carlson

2018

Clinical Genetics

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Split-hand/foot malformation (SHFM) is caused by mutations in TP63, DLX5, DLX6, FGF8, FGFR1, WNT10B, and BHLHA9. The clinical features of SHFM caused by mutations of these genes are not distinguishable. This implies that in normal situations these SHFM-associated genes share an underlying regulatory pathway that is involved in the development of the central parts of the hands and feet. The mutations in SHFM-related genes lead to dysregulation of Fgf8 in the central portion of the apical ectodermal ridge (AER) and subsequently lead to misexpression of a number of downstream target genes, failure of stratification of the AER, and thus SHFM. Syndactyly of the remaining digits is most likely the effects of dysregulation of Fgf-Bmp-Msx signaling on apoptotic cell death. Loss of digit identity in SHFM is hypothesized to be the effects of misexpression of HOX genes, abnormal SHH gradient, or the loss of balance between GLI3A and GLI3R. Disruption of canonical and non-canonical Wnt signaling is involved in the pathogenesis of SHFM. Whatever the causative genes of SHFM are, the mutations seem to lead to dysregulation of Fgf8 in AER cells of the central parts of the hands and feet and disruption of Wnt-Bmp-Fgf signaling pathways in AER.

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First direct evidence of involvement of a homozygous loss‐of‐function variant in the EPS15L1 gene underlying split‐hand/split‐foot malformation

Cited by 20 publications

References 24 publications

Endocytic Adaptor Proteins in Health and Disease: Lessons from Model Organisms and Human Mutations

Endocytic Adaptor Proteins in Health and Disease: Lessons from Model Organisms and Human Mutations

Exome sequencing revealed a novel loss‐of‐function variant in the GLI3 transcriptional activator 2 domain underlies nonsyndromic postaxial polydactyly

Genetic regulatory pathways of split‐hand/foot malformation

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