PEHO syndrome caused by compound heterozygote variants in ZNHIT3 gene

Abstract

PEHO syndrome is characterized by Progressive Encephalopathy with Edema, Hypsarrhythmia, and Optic atrophy, which was first described in Finnish patients. A homozygous missense substitution p.Ser31Leu in ZNHIT3 was recently identified as the primary cause of PEHO syndrome in Finland. Variants in ZNHIT3 have not been identified in patients with PEHO or PEHO-like syndrome in other populations. It has therefore been suggested that PEHO syndrome caused by ZNHIT3 variants does not occur outside of the Finnish population. We describe the first patient outside Finland who carries compound heterozygous variants in ZNHIT3 gene causing PEHO syndrome. Trio genome sequencing was carried out and the identified variants were confirmed by Sanger sequencing. The patient filled all diagnostic clinical criteria of PEHO syndrome. We identified biallelic missense variants in ZNHIT3 gene: the c.92C>T p.( Ser31Leu) variant (NM_004773.3), which is described previously as causing PEHO syndrome and the second novel variant c.41G>T p.(Cys14Phe). There are only eight heterozygous carriers of c.41G>T

Studies of mutations of assembly factor Hit1 in budding yeast suggest translation defects as the molecular basis for PEHO syndrome

“…1 A ). The PEHO syndrome-causing missense mutations, which result in the ZNHIT3 variants C14F and S31L, lie within the highly conserved Zf-HIT domain of ZNHIT3 ( 26 , 29 , 30 ), which shares 33% sequence identity and 45% sequence similarity between human and yeast ( Fig. 1 B ).…”

“…The majority of the studied ZNHIT3-associated PEHO syndrome cases to date are caused by homozygous expression of the ZNHIT3-S31L variant (yeast Hit1-S29L) (33). PEHO syndrome can also be caused by the compound heterozygous variants J o u r n a l P r e -p r o o f C14F and S31L (30). Because the phenotype of yeast cells expressing the Hit1-C11F variant is more severe than that of the Hit1-S29L variant, we anticipate that homozygous ZNHIT3-C14F variants may be incompatible with survival and thus underrepresented in patients.…”

“…Consistent with the critical role of Hit1, deletion of the HIT1 gene in yeast results in low steady-state levels of box C/D snoRNAs and impairs both box C/D snoRNP assembly and ribosome biogenesis ( 24 ). Furthermore, mutations in the ZNHIT3 gene, which encodes the human homolog of Hit1, cause a severe neurodevelopmental disorder termed PEHO syndrome (progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy) ( 29 , 30 ).…”

“…PEHO syndrome is a rare and fatal autosomal recessive disease characterized by progressive cerebellar atrophy, infantile spasms, arrest of psychomotor development, and a poor prognosis ( 31 , 32 , 33 ). ZNHIT3-associated amino acid variations that cause PEHO syndrome are found within the Zf-HIT domain of the protein ( 29 , 30 ). These include the missense variation Ser31Leu (S31L) ( 29 ) and the compound heterozygous ZNHIT3 variants S31L and Cys14Phe (C14F) ( 30 ).…”

“…ZNHIT3-associated amino acid variations that cause PEHO syndrome are found within the Zf-HIT domain of the protein ( 29 , 30 ). These include the missense variation Ser31Leu (S31L) ( 29 ) and the compound heterozygous ZNHIT3 variants S31L and Cys14Phe (C14F) ( 30 ). The ZNHIT3 missense variant S31L is also found in a class of diseases with similar phenotypes to PEHO syndrome called PEHO-like syndrome ( 33 ).…”