ITPase deficiency causes a Martsolf-like syndrome with a lethal infantile dilated cardiomyopathy.

Mark T Handley,Robert W Taylor,David R Fitzpatrick,Jimi Wills,Andrew P Jackson,Phillip Cox,Elisabeth Rosser,Mihail Halachev,Archith Kamath,Alison Meynert,Andrew J Finch,Irene Aligianis,Denise Williams,Alex Von Kriegsheim,Gavin Falkous,Kaalak Reddy,Harris Morrison,Emma Allan,S D M Brown ,Eleanor S Raymond ,Bernard Ramsahoye

doi:10.1371/journal.pgen.1007605

Abstract

Typical Martsolf syndrome is characterized by congenital cataracts, postnatal microcephaly, developmental delay, hypotonia, short stature and biallelic hypomorphic mutations in either RAB3GAP1 or RAB3GAP2. Genetic analysis of 85 unrelated “mutation negative” probands with Martsolf or Martsolf-like syndromes identified two individuals with different homozygous null mutations in ITPA, the gene encoding inosine triphosphate pyrophosphatase (ITPase). Both probands were from multiplex families with a consistent, lethal and highly distinctive disorder; a Martsolf-like syndrome with infantile-onset dilated cardiomyopathy. Severe ITPase-deficiency has been previously reported with infantile epileptic encephalopathy (MIM 616647). ITPase acts to prevent incorporation of inosine bases (rI/dI) into RNA and DNA. In Itpa-null cells dI was undetectable in genomic DNA. dI could be identified at a low level in mtDNA without detectable mitochondrial genome instability, mtDNA depletion or biochemical dysfunction of the mitochondria. rI accumulation was detectable in proband-derived lymphoblastoid RNA. In Itpa-null mouse embryos rI was detectable in the brain and kidney with the highest level seen in the embryonic heart (rI at 1 in 385 bases). Transcriptome and proteome analysis in mutant cells revealed no major differences with controls. The rate of transcription and the total amount of cellular RNA also appeared normal. rI accumulation in RNA–and by implication rI production—correlates with the severity of organ dysfunction in ITPase deficiency but the basis of the cellulopathy remains cryptic. While we cannot exclude cumulative minor effects, there are no major anomalies in the production, processing, stability and/or translation of mRNA.

Highlights

It is 40 years since two brothers were reported with severely delayed neurocognitive development, spasticity, postnatal microcephaly, short stature, congenital cataracts and primary hypogonadism[1], characterising a disorder that is termed Martsolf syndrome (MIM 212720)
We describe two unrelated families with complete loss of inosine triphosphate pyrophosphatase (ITPase) function as a consequence of disruptive mutations affecting both alleles of ITPA, the gene that encodes this protein
Both of the families have a very distinctive and severe combination of clinical problems, most notably a failure of heart muscle that was lethal in infancy or early childhood

Summary

Introduction

It is 40 years since two brothers were reported with severely delayed neurocognitive development, spasticity, postnatal microcephaly, short stature, congenital cataracts and primary hypogonadism[1], characterising a disorder that is termed Martsolf syndrome (MIM 212720). Warburg Micro syndrome (MIM 600118, 614225, 615222, 615663) is an overlapping condition that was described in 1993, which has microphthalmia/microcornea, retinal dystrophy, optic nerve atrophy and intracranial malformations as clinical features[2]. 60% of cases referred to us with a diagnosis of Warburg Micro syndrome have loss-of-function mutations in either RAB3GAP1, RAB3GAP2, RAB18 or TBC1D20[3,4,5,6]. 44% of Martsolf syndrome cases have mutations in RAB3GAP1 or RAB3GAP2, which perturb but do not completely abolish the expression or function of the encoded protein[7, 8]. Genetic testing is recommended in iDCM as it may help direct the clinical management[13]

Methods

Results

Discussion

Conclusion