YIF1B mutations cause a post-natal neurodevelopmental syndrome associated with Golgi and primary cilium alterations

Abstract

Human post-natal neurodevelopmental delay is often associated with cerebral alterations that can lead, by themselves or associated with peripheral deficits, to premature death. Here, we report the clinical features of 10 patients from six independent families with mutations in the autosomal YIF1B gene encoding a ubiquitous protein involved in anterograde traffic from the endoplasmic reticulum to the cell membrane, and in Golgi apparatus morphology. The patients displayed global developmental delay, motor delay, visual deficits with brain MRI evidence of ventricle enlargement, myelination alterations and cerebellar atrophy. A similar profile was observed in the Yif1b knockout (KO) mouse model developed to identify the cellular alterations involved in the clinical defects. In the CNS, mice lacking Yif1b displayed neuronal reduction, altered myelination of the motor cortex, cerebellar atrophy, enlargement of the ventricles, and subcellular alterations of endoplasmic reticulum and Golgi apparatus compartments. Remarkably, although YIF1B was not detected in primary cilia, biallelic YIF1B mutations caused primary cilia abnormalities in skin fibroblasts from both patients and Yif1b-KO mice, and in ciliary architectural components in the Yif1b-KO brain. Consequently, our findings identify YIF1B as an essential gene in early post-natal development in human, and provide a new genetic target that should be tested in patients developing a neurodevelopmental delay during the first year of life. Thus, our work is the first description of a functional deficit linking Golgipathies and ciliopathies, diseases so far associated exclusively to mutations in genes coding for proteins expressed within the primary cilium or related ultrastructures. We therefore propose that these pathologies should be considered as belonging to a larger class of neurodevelopmental diseases depending on proteins involved in the trafficking of proteins towards specific cell membrane compartments.

Clinical and genetic findings in patients with congenital cataract and heart diseases

“…However, patient 8 with a POLG mutation did not present weakness of the external eye muscles or exercise intolerance. Biallelic mutations of YIF1B could lead to an autosomal recessive neurodevelopmental disorder, Kara-Barakat-Masson syndrome (KABAMAS), characterized by global developmental delay, motor delay, ocular abnormalities, and nervous system change [ 23 , 24 ]. The visual deficits in KABAMAS included strabismus, optic atrophy, eye to eye contact, nystagmus.…”

“…The visual deficits in KABAMAS included strabismus, optic atrophy, eye to eye contact, nystagmus. However, a cataract was not reported in KABAMAS patients [ 24 ]. Patient 10 carrying a heterozygous mutation of YIF1B, and present no typical KABAMAS clinical manifestations.…”

Expanding the mutational landscape and clinical phenotype of the YIF1B related brain disorder

“…Interestingly, both p.Ala63fs and p.Glu200* are recurrent variants, identified in five and three independent families, respectively. 1 , 2 The p.Ala63fs variant was previously found in four Arab families, and given historic migrations of Arabs to Spain this might suggest a founder mutation. Similar, all families harbouring p.Glu200* are from Somali descent, likely indicating a founder mechanism.…”

“…All currently known YIF1B variants from Almuhaizea et al 2 and Diaz et al . 1 (blue) and those reported herein (orange) encountered in individuals with Kaya-Barakat-Masson syndrome are indicated. Missense and truncating variants are indicated with circles and triangles, respectively.…”

“…With great interest we read the article by Diaz and colleagues 1 providing further evidence of a neurodevelopmental disorder caused by bi-allelic variants disrupting the function of YIF1B , by reporting a second patient cohort and a mouse model. We had earlier reported six individuals from five unrelated families, harbouring bi-allelic protein truncating mutations in YIF1B , presenting with a progressive encephalopathy with various degrees of movement disorders, microcephaly and epilepsy.…”