KIAA0586 is Mutated in Joubert Syndrome
Human Mutation, cilt.36, sa.9, ss.831-835, 2015 (SCI-Expanded, Scopus)
- Yayın Türü: Makale / Tam Makale
- Cilt numarası: 36 Sayı: 9
- Basım Tarihi: 2015
- Doi Numarası: 10.1002/humu.22821
- Dergi Adı: Human Mutation
- Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus
- Sayfa Sayıları: ss.831-835
- Anahtar Kelimeler: Joubert syndrome, KIAA0586, Talpid3, ciliopathy, sonic hedgehog
- Sağlık Bilimleri Üniversitesi Adresli: Hayır
Özet
Joubert syndrome (JS) is a recessive neurodevelopmental disorder characterized by a distinctive mid-hindbrain malformation. JS is part of a group of disorders called ciliopathies based on their overlapping phenotypes and common underlying pathophysiology linked to primary cilium dysfunction. Biallelic mutations in one of 28 genes, all encoding proteins localizing to the primary cilium or basal body, can cause JS. Despite this large number of genes, the genetic cause can currently be determined in about 62% of individuals with JS. To identify novel JS genes, we performed whole exome sequencing on 35 individuals with JS and found biallelic rare deleterious variants (RDVs) in KIAA0586, encoding a centrosomal protein required for ciliogenesis, in one individual. Targeted next-generation sequencing in a large JS cohort identified biallelic RDVs in eight additional families for an estimated prevalence of 2.5% (9/366 JS families). All affected individuals displayed JS phenotypes toward the mild end of the spectrum. Mutations in K1AA0586 cause ∼2.5% of the neurodevelopmental disorder Joubert syndrome, a recessive ciliopathy defined by a distinctive mid-hindbrain malformation (the "molar tooth sign""). K1AA0586 encodes a centrosomal protein required for ciliogenesis and hedgehog signaling. Despite the predominance of truncating mutations, the patients do not display the neural tube patterning defects, cystic kidney disease, laterality defects, and polydactyly observed in animal models.