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Compound heterozygous splice site variants in the SCLT1 gene highlight an additional candidate locus for Senior-Loken syndrome.

ABSTRACT: Senior Løken syndrome (SLS) is a heterogeneous disorder characterized by severe retinal degenerations and juvenile-onset nephronophthisis. Genetic variants in ten different genes have been reported as the causes of SLS. Clinical evaluation of a patient with SLS and her unaffected parents revealed that the patient had infantile-onset retinal dystrophy and juvenile-onset nephronophthisis. Other systemic abnormalities included hepatic dysfunction, megacystis, mild learning disability, autism, obesity, and hyperinsulinemia. Whole-exome sequencing identified compound heterozygous SCLT1 variants (c.1218?+?3insT and c.1631A?>?G) in the patient. The unaffected parents were heterozygous for each variant. Transcript analysis using reverse transcription PCR demonstrated that the c.1218?+?3insT variant leads to exon 14 skipping (p.V383_M406del), while the other variant (c.1631A?>?G) primarily leads to exon 17 skipping (p.D480EfsX11) as well as minor amounts of two transcripts (6?bps deletion in the last of exon 17 [p.V543_K544del] and exons 17 and 18 skipping [p.D480E, S481_K610del]). Immunohistochemical analysis demonstrated that the Sclt1 protein was localized to the distal appendage of the photoreceptor basal body, indicating a ciliary protein. In conclusion, we identified compound heterozygous splice site variants of SCLT1 in a patient with a new form of ciliopathies that exhibits clinical features of SLS.

SUBMITTER: Katagiri S

PROVIDER: S-EPMC6233217 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Compound heterozygous splice site variants in the SCLT1 gene highlight an additional candidate locus for Senior-Løken syndrome.

Katagiri Satoshi S Hayashi Takaaki T Yoshitake Kazutoshi K Murai Noriyuki N Matsui Zenichi Z Kubo Hiroyuki H Satoh Hiroyuki H Matsufuji Senya S Takamura Tsuyoshi T Yokoo Takashi T Omori Yoshihiro Y Furukawa Takahisa T Iwata Takeshi T Nakano Tadashi T

Scientific reports 20181113 1

Senior Løken syndrome (SLS) is a heterogeneous disorder characterized by severe retinal degenerations and juvenile-onset nephronophthisis. Genetic variants in ten different genes have been reported as the causes of SLS. Clinical evaluation of a patient with SLS and her unaffected parents revealed that the patient had infantile-onset retinal dystrophy and juvenile-onset nephronophthisis. Other systemic abnormalities included hepatic dysfunction, megacystis, mild learning disability, autism, obesi ...[more]

PMID: 30425282

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Project description:BackgroundPathogenic variants in the TPM3 gene, encoding slow skeletal muscle α-tropomyosin account for less than 5% of nemaline myopathy cases. Dominantly inherited or de novo missense variants in TPM3 are more common than recessive loss-of-function variants. The recessive variants reported to date seem to affect either the 5' or the 3' end of the skeletal muscle-specific TPM3 transcript.ObjectivesThe aim of the study was to identify the disease-causing gene and variants in a Finnish patient with an unusual form of nemaline myopathy.MethodsThe genetic analyses included Sanger sequencing, whole-exome sequencing, targeted array-CGH, and linked-read whole genome sequencing. RNA sequencing was done on total RNA extracted from cultured myoblasts and myotubes of the patient and controls. TPM3 protein expression was assessed by Western blot analysis. The diagnostic muscle biopsy was analyzed by routine histopathological methods.ResultsThe patient had poor head control and failure to thrive, but no hypomimia, and his upper limbs were clearly weaker than his lower limbs, features which in combination with the histopathology suggested TPM3-caused nemaline myopathy. Muscle histopathology showed increased fiber size variation and numerous nemaline bodies predominantly in small type 1 fibers. The patient was found to be compound heterozygous for two splice-site variants in intron 1a of TPM3: NM_152263.4:c.117+2_5delTAGG, deleting the donor splice site of intron 1a, and NM_152263.4:c.117 + 164 C>T, which activates an acceptor splice site preceding a non-coding exon in intron 1a. RNA sequencing revealed inclusion of intron 1a and the non-coding exon in the transcripts, resulting in early premature stop codons. Western blot using patient myoblasts revealed markedly reduced levels of the TPM3 protein.ConclusionsNovel biallelic splice-site variants were shown to markedly reduce TPM3 protein expression. The effects of the variants on splicing were readily revealed by RNA sequencing, demonstrating the power of the method.

Dataset Information

Compound heterozygous splice site variants in the SCLT1 gene highlight an additional candidate locus for Senior-Loken syndrome.

Publications

Compound heterozygous splice site variants in the SCLT1 gene highlight an additional candidate locus for Senior-Løken syndrome.

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