A further family of Stromme syndrome carrying CENPF mutation

Abstract

Stromme syndrome is a rare genetic disorder characterized by microcephaly, anterior ocular chamber anomalies, and "apple peel" type jejunal atresia. Here, we report a Stromme syndrome family with two affected siblings with a homozygous truncating frameshift mutation in CENPF. A 3-month-old girl was hospitalized due to prenatally diagnosed microcephaly, microphthalmia, and dysmorphological features. The history of a previous child with the same findings in addition to "apple peel" intestinal atresia had been noted. Regarding the clinical features of both affected siblings, a diagnosis of Stromme syndrome was established. Exome-sequencing of these two cases showed the homozygous mutation (c.5912_5913insA)/(p.T1974Nfs*9) in CENPF. While confirmation of this gene being responsible for Stromme syndrome was pending our results, Filges et al. reported that CENPF was indeed underlying the reason for Stromme syndrome. This is the second case report identifying CENPF mutation as the cause of Stromme syndrome.

Miro-dependent mitochondrial pool of CENP-F and its farnesylated C-terminal domain are dispensable for normal development in mice

“…CENP-F is also involved in human genetic diseases (Aytes et al, 2014;Filges et al, 2016;Ozkinay et al, 2017;Waters et al, 2015). In particular, familial mutations in human CENP-F lead to the Strømme syndrome, a disease characterized by severe ciliopathy phenotypes such as microcephaly and intestinal atresia.…”

“…In humans, aberrant expression of CENP-F has been implicated in prostate cancer (Aytes et al, 2014). In addition, mutations in CENP-F are known to cause Strømme syndrome, a rare autosomal recessive disorder characterized by microcephaly, intestinal atresia and other ciliopathy phenotypes (Filges et al, 2016;Ozkinay et al, 2017;Waters et al, 2015).…”

The Mitotic Apparatus and Kinetochores in Microcephaly and Neurodevelopmental Diseases

“…Several clinically relevant mutations of CENP-F have been identified in Stromme Syndrome, which is a severe disease affecting multiple systems that feature a ciliopathy and microcephaly [5,127,128]. Remarkably, these mutations fall in the N-terminal domain of CENP-F, which contains the MT-binding domain [5,127] or in the C-terminal domain, harboring both the NLS and the neighboring KEN degradation sequence [128]. Of those, one frameshift mutation produces a truncated protein devoid of the NLS signal [128], and two point mutations may affect the NLS function [5] (see the map in Figure 1).…”

“…Remarkably, these mutations fall in the N-terminal domain of CENP-F, which contains the MT-binding domain [5,127] or in the C-terminal domain, harboring both the NLS and the neighboring KEN degradation sequence [128]. Of those, one frameshift mutation produces a truncated protein devoid of the NLS signal [128], and two point mutations may affect the NLS function [5] (see the map in Figure 1).…”

CUGC for Stromme syndrome and CENPF-related disorders

“…still hard to provide. The phenotypes range from isolated primary microcephaly, the clinical triad of Stromme syndrome including microcephaly, ocular anomalies and intestinal atresia to a variable ciliopathy phenotype including brain anomalies (such as hydrocephalus, cerebellar hypoplasia, agenesis of the corpus callosum), cleft palate, polydactyly, renal dysplasia and duodenal/intestinal atresia, which may be fetal lethal at the severe end of the spectrum [1][2][3][4][5][6][7]. Inheritance is autosomal recessive and all variants affecting function in affected individuals described to date are truncating variants (nonsense/stop, splice site, deletion and insertion sequence variants) [1][2][3][8][9][10]].…”