title: Homozygous mutation in SAMHD1 gene causes cerebral vasculopathy and early onset stroke.
abstract: We describe an autosomal recessive condition characterized with cerebral vasculopathy and early onset of stroke in 14 individuals in Old Order Amish. The phenotype of the condition was highly heterogeneous, ranging from severe developmental disability to normal schooling. Cerebral vasculopathy was a major hallmark of the condition with a common theme of multifocal stenoses and aneurysms in large arteries, accompanied by chronic ischemic changes, moyamoya morphology, and evidence of prior acute infarction and hemorrhage. Early signs of the disease included mild intrauterine growth restriction, infantile hypotonia, and irritability, followed by failure to thrive and short stature. Acrocyanosis, Raynaud's phenomenon, chilblain lesions, low-pitch hoarse voice, glaucoma, migraine headache, and arthritis were frequently observed. The early onset or recurrence of strokes secondary to cerebral vasculopathy seems to always be associated with poor outcomes. The elevated erythrocyte sedimentation rate (ESR), IgG, neopterin, and TNF-α found in these patients suggested an immune disorder. Through genomewide homozygosity mapping, we localized the disease gene to chromosome (Chr) 20q11.22-q12. Candidate gene sequencing identified a homozygous mutation, c.1411-2A > G, in the SAMHD1 gene, being associated with this condition. The mutation appeared at the splice-acceptor site of intron 12, resulted in the skipping of exon 13, and gave rise to an aberrant protein with in-frame deletion of 31 amino acids. Immunoblotting analysis showed lack of mutant SAMHD1 protein expression in affected cell lines. The function of SAMHD1 remains unclear, but the inflammatory vasculopathies of the brain found in the patients with SAMHD1 mutation indicate its important roles in immunoregulation and cerebral vascular hemeostasis.
authors.affiliation: DDC Clinic for Special Needs Children, Middlefield, OH 44062, USA.
authors.forename: Baozhong
authors.initials: B
authors.lastname: Xin
authors.forename: Stephen
authors.initials: S
authors.lastname: Jones
authors.forename: Erik G
authors.initials: EG
authors.lastname: Puffenberger
authors.forename: Claas
authors.initials: C
authors.lastname: Hinze
authors.forename: Alicia
authors.initials: A
authors.lastname: Bright
authors.forename: Haiyan
authors.initials: H
authors.lastname: Tan
authors.forename: Aimin
authors.initials: A
authors.lastname: Zhou
authors.forename: Guiyun
authors.initials: G
authors.lastname: Wu
authors.forename: Jilda
authors.initials: J
authors.lastname: Vargus-Adams
authors.forename: Dimitris
authors.initials: D
authors.lastname: Agamanolis
authors.forename: Heng
authors.initials: H
authors.lastname: Wang
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D001483:Base Sequence; D002560:Cerebrovascular Circulation; D002561:Cerebrovascular Disorders / Q000235:genetics* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005006:Ethnicity / Q000235:genetics; D005260:Female; D006720:Homozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D000076106:SAM Domain and HD Domain-Containing Protein 1; D020521:Stroke / Q000235:genetics* / Q000473:pathology; D055815:Young Adult
chemical_list: D000076106:SAM Domain and HD Domain-Containing Protein 1; C484280:SAMHD1 protein, human; D020559:Monomeric GTP-Binding Proteins