Biallelic loss-of-function mutations in JAM2 cause primary familial brain calcification.

Primary familial brain calcification is a monogenic disease characterized by bilateral calcifications in the basal ganglia and other brain regions, and commonly presents motor, psychiatric, and cognitive symptoms. Currently, four autosomal dominant (SLC20A2, PDGFRB, PDGFB, XPR1) and one autosomal recessive (MYORG) causative genes have been identified. Compared with patients with autosomal dominant primary familial brain calcification, patients with the recessive form of the disease present with more severe clinical and imaging phenotypes, and deserve more clinical and research attention. Biallelic mutations in MYORG cannot explain all autosomal recessive primary familial brain calcification cases, indicating the existence of novel autosomal recessive genes. Using homozygosity mapping and whole genome sequencing, we detected a homozygous frameshift mutation (c.140delT, p.L48*) in the JAM2 gene in a consanguineous family with two affected siblings diagnosed with primary familial brain calcification. Further genetic screening in a cohort of 398 probands detected a homozygous start codon mutation (c.1A>G, p.M1?) and compound heterozygous mutations [c.504G>C, p.W168C and c.(67+1_68-1)_(394+1_395-1), p.Y23_V131delinsL], respectively, in two unrelated families. The clinical phenotypes of the four patients included parkinsonism (3/4), dysarthria (3/4), seizures (1/4), and probable asymptomatic (1/4), with diverse onset ages. All patients presented with severe calcifications in the cortex in addition to extensive calcifications in multiple brain areas (lenticular nuclei, caudate nuclei, thalamus, cerebellar hemispheres, ± brainstem; total calcification scores: 43-77). JAM2 encodes junctional adhesion molecule 2, which is highly expressed in neurovascular unit-related cell types (endothelial cells and astrocytes) and is predominantly localized on the plasma membrane. It may be important in cell-cell adhesion and maintaining homeostasis in the CNS. In Chinese hamster ovary cells, truncated His-tagged JAM2 proteins were detected by western blot following transfection of p.Y23_V131delinsL mutant plasmid, while no protein was detected following transfection of p.L48* or p.1M? mutant plasmids. In immunofluorescence experiments, the p.W168C mutant JAM2 protein failed to translocate to the plasma membrane. We speculated that mutant JAM2 protein resulted in impaired cell-cell adhesion functions and reduced integrity of the neurovascular unit. This is similar to the mechanisms of other causative genes for primary familial brain calcification or brain calcification syndromes (e.g. PDGFRB, PDGFB, MYORG, JAM3, and OCLN), all of which are highly expressed and functionally important in the neurovascular unit. Our study identifies a novel causative gene for primary familial brain calcification, whose vital function and high expression in the neurovascular unit further supports impairment of the neurovascular unit as the root of primary familial brain calcification pathogenesis.

LRP10 in autosomal-dominant Parkinson's disease.

BACKGROUND: Recently, the LRP10 gene has been identified as a novel genetic cause in individuals affected by Parkinson's disease (PD), Parkinson's disease dementia, or dementia with Lewy bodies. OBJECTIVE: We investigated the involvement of LRP10 mutations in Chinese patients with familial PD and reviewed previous studies of LRP10 mutations in patients with PD. METHODS: A mutation analysis of the LRP10 gene was performed in a cohort of 205 unrelated Chinese patients with familial PD. Burden analysis was conducted using data from the Genome Aggregation Database and 5 genetic studies of LRP10 in patients with PD (including our cohort). RESULTS: A total of 3 novel potentially pathogenic variants, c.32T>A (p.L11H), c.1184G>A (p.R395H), and c.1333G>A (p.A445T), were detected in 3 probands of our cohort. However, burden analysis argued against an overrepresentation of variant alleles in patients with PD. CONCLUSIONS: Genetic screening of the LRP10 gene in our cohort may provide independent, albeit limited, evidence for the pathogenicity of LRP10 in familial PD. Burden analysis using data from current studies failed to support the association between LRP10 and PD in general. Thus, more robust replication studies are warranted to determine the involvement of LRP10 in the pathogenesis of PD. © 2019 International Parkinson and Movement Disorder Society.

[Genetic analysis of a pedigree affected with X-linked adrenoleukodystrophy].

OBJECTIVE: To explore the genetic basis for a pedigree affected with X-linked adrenoleukodystrophy presenting as spastic paraplegia of the lower limbs. METHODS: Genomic DNA was extracted from peripheral blood samples of the patient and his mother. Potential variant was detected with a panel for genes associated with spastic paraplegia. Candidate variant was verified by PCR and Sanger sequencing. RESULTS: Both the proband and his mother presented with walking difficulty. A previously known variant, c.623T to A (p.V208E), was identified in the ABCD1 gene mapped on chromosome X in both. CONCLUSION: X-link adrenoleukodystrophy should be taken into account as a possible diagnosis for this pedigree.