Balkan Journal of Medical Genetics

SARCOLEMMAL DEFICIENCY OF SARCOGLYCAN COMPLEX IN AN 18-MONTH-OLD TURKISH BOY WITH A LARGE DELETION IN THE BETA SARCOGLYCAN GENE
Diniz G1,*, Tekgul H2, Hazan F3, Yararbas K4, Tukun A5
*Corresponding Author: Associate Professor Gulden Diniz, Neuromuscular Disease Center, Tepecik Research Hospital, Kibris Sehitleri Cad. 51/11 Alsancak 35220, Izmir, Turkey. Tel: +90-232-362-5547. Fax: +90-232-362- 7144. E-mail: agdiniz@gmail.com
page: 71

INTRODUCTION

Limb girdle muscular dystrophy type 2E (LGMD- 2E) is an autosomal recessive muscular disease caused by genetic defects in the beta sarcoglycan (SGCB) gene. The SGCB gene, which encodes instructions for making the β subunit of the sarcolemmal proteins called the sarcoglycans (SGCs), located on chromosome 4q12 [1,2]. β Sarcoglycan (β-SGC), one of the four SGCs, is essential for membrane integrity during muscle contraction and provides a scaffold for important signaling molecules [1-3]. The LGMD-2E predominantly affects proximal muscles around the scapular and the pelvic girdles and has a very heterogeneous phenotype. The age of onset, rate of progression and the severity of disease can vary between and also within affected families [1-4]. Complex mechanisms have been postulated for the development of the clinical heterogenity of LGMD-2E. A mutation in any SGC gene can lead to a reduction of the other SGCs [4-8]. The sarcoglycan- sarcospan and dystroglycan complexes were disrupted in skeletal, cardiac and smooth muscle membranes. It is suggested that the SGCB gene must first be evaluated if there is a total absence of SGCs [4]. Here we present a milder phenotype of LGMD-2E with a large deletion in the SGCB gene, which provides additional support for the clinical heterogeneity and complex pathogenicity of the disease. Case Report. A 12-month-old boy had an increased serum creatine phosphokinase (CPK) without symptoms. Persistent elevation of CPK values prompted muscle biopsy at 18 months of age. He had second degree consanguineous parents from Turkey without an ancestral history of neuromuscular disorders. Cognitive and motor development was normal. Deep tendon reflexes were present and he had no contractures. He started walking at 14 months of age and was walking normally. Pulmonary function tests were normal. His CPK levels were between 9000 and 11,000 U/L (normal <250 U/L), and there was evidence of myopathy on electromyography (EMG). Because of the persistent high CPK level, muscular dystrophy (MD) was suspected and, after informed consent, samples were obtained for histopathology, immunohistochemistry and molecular genetics testing. The histopathological evaluation was performed on the biopsy from the gastrocnemius muscle. The biopsy specimen was frozen in isopentane that was pre-cooled to ‒160 °C in liquid nitrogen. Cryosections were immunostained for dystrophin using a polyclonal antibody (Neomarkers-PA137587; Thermo Scientific, Waltham, MA, USA), with a monoclonal spectrin antibody (Novocastra-SPECT; Leica Biosystems, Wetzlar, Germany) as a control. The SGCs were detected with anti α-, β-, δ- and γ- SGC antibodies (Novocastra-A,B,D OR G-SARC-CE). The muscle biopsy showed dystrophic changes such as contraction, regeneration, degeneration, necrosis, nuclear internalization and fibrosis (Figure 1). Immunohistochemically, sarcolemmal dystrophin and spectrin expressions were present at normal levels, whereas sarcolemmal α-, β-, δ- and γ-SGCs were diffusely absent or there was abnormal sarcoplasmic staining in some myofibers (Figure 2). Genomic DNA was extracted from the remnant muscle tissue using a commercial DNA extraction kit (QiaGen; Qiagen Inc., Valencia, CA, USA) following the standard manufacturer’s protocol. The concentration of sample DNA was determined by a Nanodrop® spectrophotometer (NanoDrop Technologies, Wilmington, DE, USA). The exon regions and flanking short intronic sequences of the SGCA, SGCB, SGCD and SGCG genes were amplified using polymerase chain reaction (PCR), followed by direct sequencing of the PCR products (Applied Biosystems, Foster City, CA, USA). The multiplex ligation-dependent probe amplification (MLPA) technique (Applied Systems), was used for deletion and duplication analysis for all four SGCs. Based on analysis of the proband, we have identified a large deletion in the SGCB gene (Figure 3). In addition, there was a heterozygous c.G860A (p.S287N) mutation in the SGCG gene that was not a disease-causing genetic defect. The results of the molecular analyses for mutations of dystrophin, α-, β- and δ-SGC genes were normal.

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