RIBITOL XYLOSYLTRANSFERASE 1; RXYLT1

TRANSMEMBRANE PROTEIN 5; TMEM5

HGNC Approved Gene Symbol: RXYLT1

Cytogenetic location: 12q14.2 Genomic coordinates (GRCh38): 12:63,779,909-63,809,562 (from NCBI)

▼ Description

The TMEM5 gene encodes a transmembrane protein believed to have glycosyltransferase function (summary by Vuillaumier-Barrot et al., 2012).

▼ Cloning and Expression

Yokoyama-Kobayashi et al. (1995) developed a system to detect N-terminal secretory signal sequences, called the fibrin sheet method, based on the detection of secreted protein fused to a urokinase plasminogen activator protein having fibrinolytic activity. Yokoyama-Kobayashi et al. (1999) adopted this system to identify cDNAs encoding type II signal anchors, in which the N-terminal signal sequence is uncleaved and remains in the membrane, facing the cytoplasm. They isolated a cDNA encoding TMEM5, which they termed HP10481, from a phorbol ester-stimulated U937 monocyte cDNA library. TMEM5 is predicted to encode a 443-amino acid type II transmembrane protein.

Vuillaumier-Barrot et al. (2012) noted that TMEM5 contains a domain encompassing amino acids 218-353 that has some similarities to exostosin (EXT1; 608177), which is a glycosyltransferase.

▼ Mapping

Amberger (2008) mapped the TMEM5 gene to chromosome 12q14.2 based on an alignment of the TMEM5 sequence (GenBank AB015633) with the genomic sequence.

▼ Molecular Genetics

In 9 fetuses with severe cobblestone lissencephaly consistent with muscular dystrophy-dystroglycanopathy type A10 (MDDGA10; 615041), Vuillaumier-Barrot et al. (2012) identified 5 different mutations in the TMEM5 gene (605862.0001-605862.0005). All mutations were in homozygous or compound heterozygous state, consistent with autosomal recessive inheritance. The first mutation was identified by homozygosity mapping combined with exome sequencing in a consanguineous family. No functional studies were performed. TMEM5 mutations accounted for 5 (9%) of 58 families with cobblestone lissencephaly in whom a genetic defect was found.

Jae et al. (2013) identified homozygous mutations in the TMEM5 gene in affected members of 2 unrelated consanguineous families with MDDGA10. In Family 43, a boy who died at age 22 months had a nonsense mutation (R340X; 605862.0006); in Family 56, 2 sisters, aged 19 and 21 years, had a frameshift mutation (605862.0007).

▼ ALLELIC VARIANTS ( 7 Selected Examples):

.0001 MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH BRAIN AND EYE ANOMALIES), TYPE A, 10
RXYLT1, 1-BP DEL, 795G

In 4 affected fetuses of a consanguineous family with congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies type A10 (MDDGA10; 615041), Vuillaumier-Barrot et al. (2012) identified a homozygous 1-bp deletion (795delG) in exon 5 of the TMEM5 gene, resulting in a frameshift and premature termination (Arg266GlyfsTer8). Each unaffected parent was heterozygous for the mutation. The mutation, which was found by homozygosity mapping and exome sequencing, was not found in several large databases.

.0002 MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH BRAIN AND EYE ANOMALIES), TYPE A, 10
RXYLT1, TYR339CYS

In 2 sib fetuses with congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies type A10 (MDDGA10; 615041), Vuillaumier-Barrot et al. (2012) identified a homozygous 1016A-G transition in exon 6 of the TMEM5 gene, resulting in a tyr339-to-cys (Y339C) substitution at a highly conserved residue. Another unrelated fetus with the disorder was compound heterozygous for Y339C and a 28-bp deletion (1064_1091del; 605862.0004) in exon 6, resulting in a frameshift and premature termination (Asp355ValfsTer33).

.0003 MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH BRAIN AND EYE ANOMALIES), TYPE A, 10
RXYLT1, ARG340LEU

In a fetus with congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies type A10 (MDDGA10; 615041), Vuillaumier-Barrot et al. (2012) identified compound heterozygosity for 2 mutations in the TMEM5 gene: a 2-bp del/ins in exon 6 (1019_1020delinsTT), resulting in an arg340-to-leu (R340L) substitution at a highly conserved residue, and a 28-bp deletion (1064_1091; 605862.0004) in exon 6, resulting in a frameshift and premature termination (Asp355ValfsTer33).

.0004 MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH BRAIN AND EYE ANOMALIES), TYPE A, 10
RXYLT1, 28-BP DEL, NT1064

For discussion of a 28-bp deletion (1064_1091del) in the TMEM5 gene that was found in compound heterozygous state in fetuses with congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies type A10 (MDDGA10; 615041) by Vuillaumier-Barrot et al. (2012), see 605862.0002 and 605862.0003.

.0005 MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH BRAIN AND EYE ANOMALIES), TYPE A, 10
RXYLT1, 1-BP DEL, 279A

In a fetus with congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies type A10 (MDDGA10; 615041), Vuillaumier-Barrot et al. (2012) identified a homozygous 1-bp deletion (279delA) in exon 2 of the TMEM5 gene, resulting in a frameshift and premature termination (Gly94GlufsTer33).

.0006 MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH BRAIN AND EYE ANOMALIES), TYPE A, 10
RXYLT1, ARG340TER

In a newborn male with congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies type A10 (MDDGA10; 615041), who died at 22 months of age, Jae et al. (2013) identified a 1018C-T transition in the TMEM5 gene, resulting in an arg340-to-ter (R340X) substitution. The parents (Family 43) were second cousins.

.0007 MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH BRAIN AND EYE ANOMALIES), TYPE A, 10
RXYLT1, 1-BP DEL, 139G

In 2 sisters with congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies type A10 (MDDGA10; 615041), Jae et al. (2013) identified a 1-bp deletion (139delG) in the TMEM5 gene, resulting in a frameshift (Ala47ArgfsTer42). Both sisters had severe intellectual disability and gait disturbances but were alive at ages 19 and 21 years. The parents (Family 56) were first cousins.