A missense mutation, p.V132G, in the X-linked spermine synthase gene (SMS) causes Snyder-Robinson syndrome

Abstract

Snyder-Robinson syndrome (SRS, OMIM 309583) is a rare X-linked syndrome characterized by mental retardation, marfanoid habitus, skeletal defects, osteoporosis, and facial asymmetry. Linkage analysis localized the related gene to Xp21.3-p22.12, and a G-to-A transition at point +5 of intron 4 of the spermine synthase gene, which caused truncation of the SMS protein and loss of enzyme activity, was identified in the original family. Here we describe another family with Snyder-Robinson syndrome in two Mexican brothers and a novel mutation (c.496T>G) in the exon 5 of the SMS gene confirming its involvement in this rare X-linked mental retardation syndrome.

Figure 1

A) Pedigree of family with clinical features of Snyder-Robinson syndrome. B) DNA electropherograms of the proband (II-2) and a normal male. The normal V132 residue is indicated in red and the G132 mutation residue is indicated in blue. C) BsaJI digestion of a PCR product of exon 5 from the family. The 445 bp band represents the normal allele (V132) and the 242 bp and 203 bp bands represent the mutant allele (G132). D) Western blot of protein isolated from lymphoblastoid cell lines. The filter was hybridized with purified SM antibody. Lane 1 is the proband, II-2; Lane 2 is the mother, I-2; Lane 3 is the affected brother, II-3; Lane 4 is the proband from the original SRS family and Lane 5 is purified His-tagged spermine synthase protein. E) Protein alignment for spermine synthase across multiple species; the V132 residue is highlighted in yellow.

Figure 2

Patient 1 (II-2); A) frontal view, note thin habitus, wide internipple distance, pectus excavatum, shortening on the right pelvic limb, and patchy pigment of skin; B) facial asymmetry, left eyelid ptosis, slightly prominent lower lip, and dysplastic ears; C) dorsal view of hands; D) feet with broad and long halluces, and hypoplastic toenails; E) and F) dorsal kyphosis and right scoliosis.

Figure 3

X-ray images of patient 1; A) lateral view of skull, note lower bone density and thick diploe, and large sella turcica; B) long, thin tubular bones, more severe on cubitus; C) note right scoliosis and dorsal vertebral compression secondary to osteoporosis; D) right shortening and bent of femur, and on the left a recent fracture with a plaque and screws; E) positional alteration on pelvis secondary to femoral shortening, diminished bone density; F) long and thin long bones.

Figure 4

Patient 2 (II-3); A) frontal view, note thin habitus, wide internipple distance, pectus excavatum, and patchy pigment of skin (right side of forehead, right inguinal groove and on lumbar region); B) facial asymmetry, left palpebral ptosis, prominent lower lip, and ears are dysplastic; C) dorsal view of hands; D) feet with broad and long halluces, and hypoplastic 2-5 toenails; E) and F) mild right scoliosis.

Figure 5

X-ray images of patient 2; A) lateral view of skull, note lower bone density and thick diploe, and large sella turcica; B) note mild right scoliosis; C) diminished bone density on pelvis bones; D) upper limbs with long and thin tubular bones; E) lower limbs with long and thin long bones.