Novel Compound Heterozygous Variants in MKS1 Leading to Joubert Syndrome

Minna Luo; Ruida He; Zaisheng Lin; Yue Shen; Guangyu Zhang; Zongfu Cao; Chao Lu; Dan Meng; Jing Zhang; Xu Ma; Muqing Cao

doi:10.3389/fgene.2020.576235

Novel Compound Heterozygous Variants in MKS1 Leading to Joubert Syndrome

Front Genet. 2020 Oct 14:11:576235. doi: 10.3389/fgene.2020.576235. eCollection 2020.

Authors

Minna Luo^{1

2}, Ruida He³, Zaisheng Lin³, Yue Shen^{1

2}, Guangyu Zhang⁴, Zongfu Cao^{1

2}, Chao Lu^{1

2}, Dan Meng⁵, Jing Zhang³, Xu Ma^{1

2}, Muqing Cao³

Affiliations

¹ National Research Institute for Family Planning, Beijing, China.
² National Human Genetic Resources Center, Beijing, China.
³ Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁴ Department of Children Rehabilitation, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
⁵ Tianjin Key Laboratory of Food and Biotechnology, School of Biotechnology and Food Science, Tianjin University of Commerce, Tianjin, China.

Abstract

Joubert syndrome (JBTS) and Meckel-Gruber syndrome (MKS) are rare recessive disorders caused by defects of cilia, and they share overlapping clinical features and allelic loci. Mutations of MKS1 contribute approximately 7% to all MKS cases and are found in some JBTS patients. Here, we describe a JBTS patient with two novel mutations of MKS1. Whole exome sequencing (WES) revealed c.191-1G > A and c.1058delG compound heterozygous variants. The patient presented with typical cerebellar vermis hypoplasia, hypotonia, and developmental delay, but without other renal/hepatic involvement or polydactyly. Functional studies showed that the c.1058delG mutation disrupts the B9 domain of MKS1, attenuates the interactions with B9D2, and impairs its ciliary localization at the transition zone (TZ), indicating that the B9 domain of MKS1 is essential for the integrity of the B9 protein complex and localization of MKS1 at the TZ. This work expands the mutation spectrum of MKS1 and elucidates the clinical heterogeneity of MKS1-related ciliopathies.

Keywords: B9 proteins; Joubert syndrome; MKS1; cilia; ciliopathy.