A Novel CCM1/KRIT1 Heterozygous Nonsense Mutation (c.1864C>T) Associated with Familial Cerebral Cavernous Malformation: a Genetic Insight from an 8-Year Continuous Observational Study

Abstract

Cerebral cavernous malformation (CCM) is a congenital vascular abnormality that predominantly affects the central nervous system, but that sometimes encroaches other vital tissues, including the retina, skin, and even liver. The familial form of CCM (FCCM) is considered to be an autosomal dominant disease with incomplete penetrance and variable expression, which is often attributed to mutations in three genes: CCM1, CCM2, and CCM3. We screened a Chinese family diagnosed with FCCM by using Sanger sequencing. A 29-year-old male proband with cutaneous angiomas was pathologically diagnosed but presented with an atypical form of CCM as revealed by magnetic resonance imaging (MRI) findings, prompting further clinical evaluation and genetic analyses of him and his immediate family. We performed continuous observation over an 8-year period using MRI gradient echo imaging and susceptibility-weighted imaging of these individuals. Sanger sequencing of the CCM1, CCM2, and CCM3 genes identified a novel heterozygous nonsense nucleotide transition (c.1864C>T; p.Gln622X) in exon 17 of the CCM1/KRIT1 gene; this mutation was predicted to cause a premature stop codon (TAG) at nucleotides 1864 to 1866 to generate a truncated Krev interaction trapped 1 (Krit1) protein of 621 amino acids. During this long-term observational study, one of the enrolled family members with neurological deficits progressed to a stage indicative of brain surgery. This study provides a new CCM gene mutation profile, which highlights the significance of genetic counseling for individuals suspected of having this condition.

A Novel PKD1 Mutation Associated With Autosomal Dominant Kidney Disease and Cerebral Cavernous Malformation

“…CCM is a vascular malformation characterized by closely clustered capillary-like channels. Clinical manifestations include seizures, hemorrhagic stroke and focal neurological deficits ( 13 ). Both sporadic and familial forms of CCM exist.…”

“…Both sporadic and familial forms of CCM exist. Familial CCM is associated with a heterozygous germline loss-of-function mutation in KRIT1 ( CCM1 ), CCM2 or PDCD10 ( CCM3 ) ( 13 ). Although loss of any CCM gene causes very similar disease phenotypes, CCM proteins are structurally distinct and share no sequence homology.…”

Identification of novel missense mutations (c.1156T>C and c.785T>C) in the PSEN1 gene in Chinese families with early-onset Alzheimer’s disease

“…Therefore, we speculate that the early-onset Alzheimer's disease observed in the two Chinese families described in the current work was caused by these novel mutations. It should be noted that in the affected families, some elderly relatives remained asymptomatic, indicating that this inherited disease caused by PSEN1 mutations may harbor an incomplete penetrance like some other autosomal dominant diseases [22]. Sun et al performed a functional study and found that the L262F mutation was associated with an increased Aβ42/Aβ40 ratio in vitro [18].…”

<p>A novel PDCD10 gene mutation in cerebral cavernous malformations: a case report and review of the literature</p>

“…5 However, only 20–30% of individuals with CCMs experience some related health problems. Generally, CCMs predominantly affect the CNS, but that sometimes affect other vital tissues, including the retina, skin, 6 and even liver. 7 …”