Biallelic mutations in EXOC3L2 cause a novel syndrome that affects the brain, kidney and blood

Abstract

BackgroundDandy-Walker malformation features agenesis/hypoplasia of the cerebellar vermis, cystic dilatation of the fourth ventricle and enlargement of posterior fossa. Although Dandy-Walker malformation is relatively common and several genes were linked to the syndrome, the genetic cause in the majority of cases is unknown.ObjectiveTo identify the mutated gene responsible for Dandy-Walker malformation, kidney disease and bone marrow failure in four patients from two unrelated families.MethodsMedical assessment, sonographic, MRI and pathological studies were used to define phenotype. Chromosomal microarray analysis and whole-exome sequence were performed to unravel the genotype.ResultsWe report four subjects from two unrelated families with homozygous mutations in the Exocyst Complex Component 3-Like-2 gene (EXOC3L2).EXOC3L2 functions in trafficking of post-Golgi vesicles to the plasma membrane. In the first family a missense mutation in a highly conserved amino acid, p.Leu41Gln, was found in three fetuses; all had severe forms of Dandy-Walker malformation that was detectable by prenatal ultrasonography and confirmed by autopsy. In the second family, the affected child carried a nonsense mutation, p.Arg72*, and no detected protein. He had peritrigonal and cerebellar white matter abnormalities with enlargement of the ventricular trigones, developmental delay, pituitary hypoplasia, severe renal dysplasia and bone marrow failure.ConclusionWe propose that biallelic EXOC3L2 mutations lead to a novel syndrome that affects hindbrain development, kidney and possibly the bone marrow.

Blood Leukocyte Counts in Alzheimer Disease

“…The genes with the 10% highest weights in the current MR IVW analysis were associated with monocyte-macrophage function including migration, cytokines, and receptors, exemplified by, among others, CCR2 , EXOC3L2 , and LYZ (eTable 7 in Supplement 2). These genes have previously been reported to associate with immunodeficiency, AD, or amyloidosis, and thus further support the present findings . The present observed associations between peripheral markers of inflammation and the development of dementia may, however, not only directly be through AD pathology.…”

“…These genes have previously been reported to associate with immunodeficiency, AD, or amyloidosis, and thus further support the present findings. 31,34,35 The present observed associations between peripheral markers of inflammation and the development of dementia may, however, not only directly be through AD pathology. Monocyte function may also predispose to other health conditions or comorbidities that ultimately influence cognition outside the AD pathogenesis.…”

Exo70 protects against memory and synaptic impairments following mild traumatic brain injury

“…A genetic anomaly of Sec15 and downregulation are involved in neurodevelopmental abnormalities related to language abilities [40][41][42]. SEC5 and SEC6 variants also affect brain development, presenting severe hypoplastic hippocampi and shrinking cerebellum [43,44]. Outside those reports, only one has studied Exocyst's involvement in neurodegenerative diseases such as Alzheimer's, where Sec6 has been associated with brain glucose metabolism abnormalities [45].…”

The exocyst complex in neurological disorders

“…In another study, novel mutations of EXOC3L2 were found in two families with Dandy–Walker malformation (DWM) (Shalata et al 2019 ) (Table 1 ), which primarily affects cerebellar development and is often associated with ciliopathies. One family was consanguineous and had three aborted fetuses, all diagnosed with DWM, carrying the homozygous c.122T > A; p.Leu41Gln mutation in EXOC3L2 .…”