Cerebroretinal Microangiopathy With Calcifications And Cysts 2

A number sign (#) is used with this entry because of evidence that cerebroretinal microangiopathy with calcifications and cysts-2 (CRMCC2) is caused by homozygous mutation in the STN1 gene (613128) on chromosome 10q24.

Description

CRMCC2 is an autosomal recessive multisystem disorder characterized by premature aging, pancytopenia, hypocellular bone marrow, osteopenia, liver fibrosis, and vascular telangiectasia resulting in gastrointestinal bleeding. Brain imaging shows intracranial calcifications and leukodystrophy, which may result in neurologic signs including spasticity, ataxia, or dystonia. Patients may also have retinal telangiectasia (summary by Simon et al., 2016).

For a discussion of genetic heterogeneity of CRMCC, see CRMCC1 (612199).

Clinical Features

Simon et al. (2016) reported 2 unrelated teenaged patients, both born of consanguineous Pakistani parents, with CRMCC2. Both patients had intrauterine growth retardation and later showed symptoms of premature aging, including poor growth and gray hair. Additional features included liver fibrosis with portal hypertension and esophageal varices, brain calcifications, white matter changes, osteopenia, pancytopenia, and hypocellular bone marrow. Both also had vascular abnormalities, including gastrointestinal hemorrhages caused by gastric antral vascular ectasia and telangiectasia resulting in recurrent gastrointestinal hemorrhage. The female patient also had neurologic symptoms, including spasticity, dystonia, and ataxia, and she died of gastrointestinal bleeding at age 16. The male patient had bilateral retinal telangiectatic changes; gastrointestinal bleeding in this patient was successfully managed with thalidomide treatment.

Inheritance

The transmission pattern of CRMCC2 in the families reported by Simon et al. (2016) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 2 unrelated patients, both born of consanguineous Pakistani parents, with CRMCC2, Simon et al. (2016) identified different homozygous missense mutations in the STN1 gene (R135T, 613128.0001 and D157Y, 613128.0002). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Patient fibroblasts were abnormally large, contained cytoplasmic vacuoles and extended podia, and grew poorly due to replication defects. The cells showed premature cellular senescence and increased apoptotic nuclei compared to controls, as well as micronuclei and torn DNA nuclear bridges. Cells showed several replication defects, including a decreased ability to release cells from S-phase and attenuation in the recovery from replication fork stalling after stress. These defects could be rescued with wildtype STN1. Telomere lengths from peripheral blood leukocytes were normal in the female patient, but shortened in the male patient; telomere lengths from fibroblasts were normal in the male patient. However, fibroblasts from both patients showed telomeric defects, such as abnormal telomere C-strand synthesis, fused chromosome ends, and telomere dysfunction-induced foci. Simon et al. (2016) suggested that the long single-stranded G-rich telomere sequences could abrogate telomere protection and activate DNA damage response and repair. Neither mutation could rescue telangiectatic defects observed in zebrafish embryos with morpholino knockdown of the stn1 gene, suggesting that both mutations resulted in a loss of function.

Animal Model

Simon et al. (2016) found that morpholino knockdown of the stn1 gene in zebrafish embryos resulted in decreased red blood cells and an arrest in T-cell progenitors, as well as increased vascularity. The vascular defects could be rescued by wildtype stn1 and by thalidomide treatment.