A number sign (#) is used with this entry because of evidence that cerebroretinal microangiopathy with calcifications and cysts-3 (CRMCC3) is caused by homozygous mutation in the POT1 gene (606478) on chromosome 7q31. One such family has been reported.

Cerebroretinal microangiopathy with calcifications and cysts-3 (CRMCC3) is an autosomal recessive disorder characterized by intrauterine growth retardation, retinal exudates, intracranial calcifications, and leukoencephalopathy. Additional features may include global developmental delay and gastrointestinal ectasias. Telomeres may be elongated, but truncated shortened telomeres are present in some tissues (Takai et al., 2016).

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

Takai et al. (2016) reported 2 sisters, born of consanguineous parents, with CRMCC3. Both had intrauterine growth retardation, retinal exudates, intracranial calcifications, and leukoencephalopathy. The older sister had gastrointestinal ectasias that caused bleeding, resulting in death at age 3 years. She also showed bone fractures. The younger sister began to deteriorate rapidly at 4 years of age, and was incontinent, unable to walk or talk, and had feeding difficulties at age 7. She also had sparse hair.

The transmission pattern of CRMCC3 in the family reported by Takai et al. (2016) was consistent with autosomal recessive inheritance.

In 2 sisters, born of consanguineous parents, with CRMCC3, Takai et al. (2016) identified a homozygous missense mutation in the POT1 gene (S322L; 606478.0013). The unaffected parents were heterozygous for the mutation. Patient fibroblasts cells showed premature senescence and contained telomere dysfunction-induced foci, indicating a DNA damage signal at the telomeres. The growth arrest could be mitigated by activation of telomerase. The mutant POT1 protein was able to interact with TPP1, localize to telomeres, and repress ATR signaling in POT1-null HeLa cells that contained telomerase. However, the mutant protein was unable to limit telomerase-mediated telomere elongation in vitro, indicating dysfunction with a separation-of-function effect. Cells carrying the mutation were defective in regulating the telomeric 5-prime C strand, causing extended 3-prime G overhangs. This resulted in stochastic telomere truncations that could be healed with expression of telomerase. Consistent with shortening of the telomeric C strand, metaphase chromosomes showed loss of telomeres synthesized by the leading DNA strand. The truncation of the telomeres and sister telomere loss during metaphase caused excessively short telomeres that likely lost the ability to protect chromosome ends. The findings were consistent with a defect in telomere end fill-in that generates truncated telomeres, which halt proliferation in cells lacking telomerase.