Genetic analysis of IRF6, a gene involved in craniofacial midline formation, in relation to pituitary and facial morphology of patients with idiopathic growth hormone deficiency

Starink, Eline; Hokken-Koelega, Anita; Visser, Theo J.; Baan, Janneke; Peeters, Robin P.; Graaff, Laura C. G. de

doi:10.1007/s11102-017-0808-8

Cited by 5 publications

(5 citation statements)

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“…Mutations in the Interferon Regulatory Factor Six ( IRF6 ) (OMIM: 607199) (Kondo et al, 2002; Ural, Bilgen, Çakmakli, & Bekerecioğlu, 2019), and Grainy Head Like Three ( GRHL3 ) (OMIM: 608317) (Peyrard‐Janvid et al, 2014) genes have been shown to cause VWS and Popliteal pterygium syndrome (PPS) (OMIM: 119500). IRF6 is the only member of the IRF gene family involved in the craniofacial development (Starink et al., 2017). It is a protein‐coding gene with a highly conserved N terminal DNA‐binding domain and a less conserved C terminal protein‐binding domain (Ben, Jabs, & Chong, 2005; Kondo et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Non‐random distribution of deleterious mutations in the DNA and protein‐binding domains of IRF6 are associated with Van Der Woude syndrome

Alade

Buxó-Martínez

Mossey

et al. 2020

Molec Gen & Gen Med

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Background The development of the face occurs during the early days of intrauterine life by the formation of facial processes from the first Pharyngeal arch. Derangement in these well‐organized fusion events results in Orofacial clefts (OFC). Van der Woude syndrome (VWS) is one of the most common causes of syndromic cleft lip and/or palate accounting for 2% of all cases. Mutations in the IRF6 gene account for 70% of cases with the majority of these mutations located in the DNA‐binding (exon 3, 4) or protein‐binding domains (exon 7–9). The current study was designed to update the list of IRF6 variants reported for VWS by compiling all the published mutations from 2013 to date as well as including the previously unreported VWS cases from Africa and Puerto Rico. Methods We used PubMed with the search terms; "Van der Woude syndrome," “Popliteal pterygium syndrome,” "IRF6," and "Orofacial cleft" to identify eligible studies. We compiled the CADD score for all the mutations to determine the percentage of deleterious variants. Results Twenty‐one new mutations were identified from nine papers. The majority of these mutations were in exon 4. Mutations in exon 3 and 4 had CADD scores between 20 and 30 and mutations in exon 7–9 had CADD scores between 30 and 40. The presence of higher CADD scores in the protein‐binding domain (exon 7–9) further confirms the crucial role played by this domain in the function of IRF6. In the new cases, we identified five IRF6 mutations, three novel missense mutations (p.Phe36Tyr, p.Lys109Thr, and p.Gln438Leu), and two previously reported nonsense mutations (p.Ser424*and p.Arg250*). Conclusion Mutations in the protein and DNA‐binding domains of IRF6 ranked among the top 0.1% and 1% most deleterious genetic mutations, respectively. Overall, these findings expand the range of VWS mutations and are important for diagnostic and counseling purposes.

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Section: Introductionmentioning

confidence: 99%

Non‐random distribution of deleterious mutations in the DNA and protein‐binding domains of IRF6 are associated with Van Der Woude syndrome

Alade

Buxó-Martínez

Mossey

et al. 2020

Molec Gen & Gen Med

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“…As many other comparisons on these kits have already been made [5][6][7] , we decided to focus our comparison in important regions to the disease we have been studying, as to shed light to researchers in this eld which approach is better to use in their cohort. For that, we selected genes that are important to pituitary development during embryogenesis, as well as genes that have been associated with hypopituitarism [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] .…”

Section: Discussionmentioning

confidence: 99%

Comparative Exome Capture Methods to Investigate Genes Involved in Hypopituitarism in a Brazilian Population

Benedetti

Jun

et al. 2021

Preprint

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Whole Exome Sequencing (WES) has been a useful tool to improve molecular diagnosis in hypopituitarism, leading to the discovery of at least 8 new genes in the last 7 years. However, some genes associated with hypopituitarism show low coverage in this methodology, limiting its use for molecular diagnosis. Our objective is to compare three library prepping kits, NimbleGen (Roche), SureSelect (Agilent) and Nextera (Illumina) examining the best performance related to sequencing quality, exon extension coverage (≥98%) and base depth read (≥20x) of 44 genes associated with hypopituitarism and 32 involved in pituitary development. Three different groups composed of 2 HapMap samples (Group 1), 2 Brazilian patients with hypopituitarism and their respective mothers (Group 2) and 109 random Brazilian samples (Group 3) were sequenced in Illumina platform. Group 1 and 3 were performed using all three library prepping kits, while group 2 was performed with NimbleGen and SureSelect. Although all technologies covered the selected genes with similar efficiency regarding poor (less than 20%) and rich (more than 80%) GC areas, SureSelect has shown to reach the most uniform coverage in the selected region with a lower level of duplicate reads, as well as a higher number of identified pathogenic variants.

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“…Similarly, other human genetic studies reported that patients with PPS caused by IRF6‐dominant negative mutations also suffer from small mandible (Escobar and Weaver, ; Mahalik and Menon, ). Furthermore, mutations in IRF6 had been linked to craniofacial and brain abnormalities in patients affected with VWS and idiopathic growth hormone deficiency (Oberoi and Vargervik, ; Nopoulos et al, ; Starink et al, ). Consistent with these findings, our previous study showed that Irf6 genetically interacts with Twist1 during craniofacial bone development and that the compound heterozygous mice for Irf6 and Twist1 have severe micrognathia (Vieira et al, ; Song et al, ; Fakhouri et al, ).…”

Section: Discussionmentioning

confidence: 99%

A cleft lip and palate gene, Irf6, is involved in osteoblast differentiation of craniofacial bone

Thompson

Mendoza

Tan

et al. 2019

Developmental Dynamics

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Background: Interferon regulatory factor 6 (IRF6) plays a critical role in embryonic tissue development, including differentiation of epithelial cells. Besides orofacial clefting due to haploinsufficiency of IRF6, recent human genetic studies indicated that mutations in IRF6 are linked to small mandible and digit abnormalities. The function of IRF6 has been well studied in oral epithelium; however, its role in craniofacial skeletal formation remains unknown. In this study, we investigated the role of Irf6 in craniofacial bone development using comparative analyses between wild‐type (WT) and Irf6‐null littermate mice. Results: Immunostaining revealed the expression of IRF6 in hypertrophic chondrocytes, osteocytes, and bone matrix of craniofacial tissues. Histological analysis of Irf6‐null mice showed a remarkable reduction in the number of lacunae, embedded osteocytes in matrices, and a reduction in mineralization during bone formation. These abnormalities may explain the decreased craniofacial bone density detected by micro‐CT, loss of incisors, and mandibular bone abnormality of Irf6‐null mice. To validate the autonomous role of IRF6 in bone, extracted primary osteoblasts from calvarial bone of WT and Irf6‐null pups showed no effect on osteoblastic viability and proliferation. However, a reduction in mineralization was detected in Irf6‐null cells. Conclusions: Altogether, these findings suggest an autonomous role of Irf6 in regulating bone differentiation and mineralization. Developmental Dynamics 248:221‐232, 2019. © 2019 Wiley Periodicals, Inc.

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Genetic analysis of IRF6, a gene involved in craniofacial midline formation, in relation to pituitary and facial morphology of patients with idiopathic growth hormone deficiency

Cited by 5 publications

References 35 publications

Non‐random distribution of deleterious mutations in the DNA and protein‐binding domains of IRF6 are associated with Van Der Woude syndrome

Non‐random distribution of deleterious mutations in the DNA and protein‐binding domains of IRF6 are associated with Van Der Woude syndrome

Comparative Exome Capture Methods to Investigate Genes Involved in Hypopituitarism in a Brazilian Population

A cleft lip and palate gene, Irf6, is involved in osteoblast differentiation of craniofacial bone

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