Identification of Mutations in TMEM5 and ISPD as a Cause of Severe Cobblestone Lissencephaly

Abstract

Cobblestone lissencephaly is a peculiar brain malformation with characteristic radiological anomalies. It is defined as cortical dysplasia that results when neuroglial overmigration into the arachnoid space forms an extracortical layer that produces agyria and/or a "cobblestone" brain surface and ventricular enlargement. Cobblestone lissencephaly is pathognomonic of a continuum of autosomal-recessive diseases characterized by cerebral, ocular, and muscular deficits. These include Walker-Warburg syndrome, muscle-eye-brain disease, and Fukuyama muscular dystrophy. Mutations in POMT1, POMT2, POMGNT1, LARGE, FKTN, and FKRP identified these diseases as alpha-dystroglycanopathies. Our exhaustive screening of these six genes, in a cohort of 90 fetal cases, led to the identification of a mutation in only 53% of the families, suggesting that other genes might also be involved. We therefore decided to perform a genome-wide study in two multiplex families. This allowed us to identify two additional genes: TMEM5 and ISPD. Because TMEM has a glycosyltransferase domain and ISPD has an isoprenoid synthase domain characteristic of nucleotide diP-sugar transferases, these two proteins are thought to be involved in the glycosylation of dystroglycan. Further screening of 40 families with cobblestone lissencephaly identified nonsense and frameshift mutations in another four unrelated cases for each gene, increasing the mutational rate to 64% in our cohort. All these cases displayed a severe phenotype of cobblestone lissencephaly A. TMEM5 mutations were frequently associated with gonadal dysgenesis and neural tube defects, and ISPD mutations were frequently associated with brain vascular anomalies.

Genetics and mechanisms leading to human cortical malformations

“…Indeed, homozygous or biallelic mutations in the GPR56 ligand, COL3A1 were also recently found associated with a COB-like malformation [228]. Nevertheless, one third of the studied COB-LIS cases has not been genetically linked to any mutation and remain unexplained [215,218]. Non-genetic causes are still recognized for COB-LIS, including prenatal vascular problems and viral infections [43].…”

“…These genes include POMT1, POMT2, POMGNT1, FKTN, FKRP, LARGE, ISPD, GTDC2, TMEM5, POMK, B4GAT1, B3GALNT2 (see Table 4) [212,213,[215][216][217][218][219][220][221][222][223][224][225]. Other mutations are rare, described in only a few patients with WWS, and include genes encoding BM constituents, such as LAMB1, LAMC3 and COL4A1, and the transmembrane and tetratricopeptide repeat containing 3 gene, TMTC3 [215,218,226], coding for a protein for which its link is currently unclear.…”

ISPD gene homozygous deletion identified by SNP array confirms prenatal manifestation of Walker–Warburg syndrome

“…Omannosylation is an important step in glycosylation and is essential for the interaction of a-dystroglycan with extracellular matrix proteins, such as laminin-a2 [Cirak et al, 2013]. Six studies of the ISPD gene mutations in patients with cobblestone lissencephaly [Vuillaumier-Barrot et al, 2012], WWS [Czeschik et al, 2013;Roscioli et al, 2012;Willer et al, 2012] and congenital and limb-girdle muscular dystrophies [Baranello et al, 2015;Cirak et al, 2013] have been published, and multiple rare variants were found in 29 independent families. All affected individuals with homozygous segmental intragenic deletion of the ISPD gene exhibited progressive muscular dystrophy with a severe WWS phenotype, including hydrocephalus, cobblestone lissencephaly of the cerebral cortex, severe brainstem hypoplasia and hypoplasia of the cerebellum cases [Roscioli et al, 2012;Willer et al, 2012].…”

“…While the WWS phenotype of the affected individuals with ISPD mutations was described for postnatal cases [Cirak et al, 2013;Czeschik et al, 2013;Roscioli et al, 2012;Willer et al, 2012], only few prenatal cases were published [Vuillaumier-Barrot et al, 2012]. We report two prenatally detected ISPD gene deletions in foetuses with multiple brain anomalies that corresponded to the WWS phenotype.…”

Gènes impliqués dans les alpha-dystroglycanopathies

“…Récemment, il a été montré que la synthèse du CDP-Ribitol ( Figure 1E), substrat pour FKRP et FKTN, est catalysée par une enzyme codée par le gène ISPD [9,45]. Ce gène avait été identifié par différentes équipes dès 2013, à partir d'études sur des patients LISII [28] ou WWS [46,47]. Des mutations du gène ISPD avaient ensuite également été identifiées chez des patients avec une clinique moins sévère, parfois sans atteinte neurologique, à l'image de ce qui est constaté pour les patients FKRP.…”