Molecular Genetics & Genomic Medicine Volume 2 Issue 3 is Published!

Molecular Genetics & Genomic Medicine has now published its next issue. Editor-in-Chief: Max Muenke introduces his editorial highlights: “This issue includes an Invited Commentary on the Future of Genomic Medicine, HLA haplotyping, Papillon-Lefèvre syndrome, and association of THAP1 mutations with Primary Dystonia. It also features the second article in our series Genetics and Genomic Medicine around the World, this month focusing on Thailand. Highlights of the issue include the articles, “Novel IRF6 Mutations in Families with Van Der Woude Syndrome and Popliteal Pterygium Syndrome from Sub-Saharan Africa”, and “Mutations of NOTCH3 in childhood pulmonary arterial hypertension”.

Novel IRF6 Mutations in Families with Van Der Woude Syndrome and Popliteal Pterygium Syndrome from Sub-Saharan Africa by Azeez Butali, Peter A. Mossey, Wasiu L. Adeyemo, Mekonen A. Eshete, LauRen A. Gaines, Dee Even, Ramat O. Braimah, Babatunde S. Aregbesola, Jennifer V. Rigdon, Christian I. Emeka, Olutayo James, Mobolanle O. Ogunlewe, Akinola L. Ladeinde, Fikre Abate, Taye Hailu, Ibrahim Mohammed, Paul E. Gravem, Milliard Deribew, Mulualem Gesses, Adebowale A. Adeyemo and Jeffrey C. Murray.
Abstract: Orofacial clefts (OFC) are complex genetic traits that are often classified as syndromic or nonsyndromic clefts. Currently, there are over 500 types of syndromic clefts in the Online Mendelian Inheritance in Man (OMIM) database, of which Van der Woude syndrome (VWS) is one of the most common (accounting for 2% of all OFC). Popliteal pterygium syndrome (PPS) is considered to be a more severe form of VWS. Mutations in the IRF6 gene have been reported worldwide to cause VWS and PPS. Here, we report studies of families with VWS and PPS in sub-Saharan Africa. We screened the DNA of eight families with VWS and one family with PPS from Nigeria and Ethiopia by Sanger sequencing of the most commonly affected exons in IRF6 (exons 3, 4, 7, and 9). For the VWS families, we found a novel nonsense variant in exon 4 (p.Lys66X), a novel splice-site variant in exon 4 (p.Pro126Pro), a novel missense variant in exon 4 (p.Phe230Leu), a previously reported splice-site variant in exon 7 that changes the acceptor splice site, and a known missense variant in exon 7 (p.Leu251Pro). A previously known missense variant was found in exon 4 (p.Arg84His) in the PPS family. All the mutations segregate in the families. Our data confirm the presence of IRF6-related VWS and PPS in sub-Saharan Africa and highlights the importance of screening for novel mutations in known genes when studying diverse global populations. This is important for counseling and prenatal diagnosis for high-risk families.

Mutations of NOTCH3 in childhood pulmonary arterial hypertension by Ayako Chida, Masaki Shintani, Yoshihisa Matsushita, Hiroki Sato, Takahiro Eitoku, Tomotaka Nakayama, Yoshiyuki Furutani, Emiko Hayama, Yoichi Kawamura, Kei Inai, Shinichi Ohtsuki, Tsutomu Saji, Shigeaki Nonoyama and Toshio Nakanishi.
Abstract: Mutations of BMPR2 and other TGF-? superfamily genes have been reported in pulmonary arterial hypertension (PAH). However, 60–90% of idiopathic PAH cases have no mutations in these genes. Recently, the expression of NOTCH3 was shown to be increased in the pulmonary artery smooth muscle cells of PAH patients. We sought to investigate NOTCH3 and its target genes in PAH patients and clarify the role of NOTCH3 signaling. We screened for mutations in NOTCH3, HES1, and HES5 in 41 PAH patients who had no mutations in BMPR2, ALK1, endoglin, SMAD1/4/8, BMPR1B, or Caveolin-1. Two novel missense mutations (c.2519 G>A p.G840E, c.2698 A>C p.T900P) in NOTCH3 were identified in two PAH patients. We performed functional analysis using stable cell lines expressing either wild-type or mutant NOTCH3. The protein-folding chaperone GRP78/BiP was colocalized with wild-type NOTCH3 in the endoplasmic reticulum, whereas the majority of GRP78/BiP was translocated into the nuclei of cells expressing mutant NOTCH3. Cell proliferation and viability were higher for cells expressing mutant NOTCH3 than for those expressing wild-type NOTCH3. We identified novel NOTCH3 mutations in PAH patients and revealed that these mutations were involved in cell proliferation and viability. NOTCH3 mutants induced an impairment in NOTCH3-HES5 signaling. The results may contribute to the elucidation of PAH pathogenesis.

The journal also publishes Genetics and Genomic Medicine around the World. Below is the second article of this type, this month focusing on Thailand.

Genetics and genomics in Thailand: challenges and opportunities” by Vorasuk Shotelersuk, Chanin Limwongse and Surakameth Mahasirimongkol

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