A mutation in the serine protease TMPRSS4 in a novel pediatric neurodegenerative disorder

Orphanet Journal of Rare Diseases

Robert A Hegele¹  Dennis E Bulman⁵  Victoria M Siu³  C Anthony Rupar³  Gregory B Gloor⁴  John F Robinson²  Jian Wang²  Lemuel Racacho⁵  Piya Lahiry⁶ 

[1]Blackburn Cardiovascular Genetics Laboratory, Robarts Research Institute, 100 Perth Drive, Room 406, London, ON N6A 5K8, Canada

[2]Robarts Research Institute, London, ON, Canada

[3]Department of Pediatrics and Children’s Health Research Institute, Lawson Health Research Institute, London, ON, Canada

[4]Department of Biochemistry, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada

[5]Departments of Pediatrics, Biochemistry, Microbiology and Immunology, University of Ottawa and Children’s Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada

[6]Department of Pediatrics, The Hospital for Sick Children, Toronto, ON, Canada

关键词: Old Order Amish;    Autosomal recessive inheritance;    Exome sequencing;    Microarray;    Homozygosity;    Trypsin-like serine protease;    Neurodegeneration;    Autosomal recessive cerebral atrophy (ARCA) syndrome;   

Others  :  863597
DOI  :  10.1186/1750-1172-8-126

 received in 2013-06-14, accepted in 2013-08-16,  发布年份 2013

【 摘 要 】

Background

To elucidate the genetic basis of a novel neurodegenerative disorder in an Old Order Amish pedigree by combining homozygosity mapping with exome sequencing.

Methods and results

We identified four individuals with an autosomal recessive condition affecting the central nervous system (CNS). Neuroimaging studies identified progressive global CNS tissue loss presenting early in life, associated with microcephaly, seizures, and psychomotor retardation; based on this, we named the condition Autosomal Recessive Cerebral Atrophy (ARCA). Using two unbiased genetic approaches, homozygosity mapping and exome sequencing, we narrowed the candidate region to chromosome 11q and identified the c.995C > T (p.Thr332Met) mutation in the TMPRSS4 gene. Sanger sequencing of additional relatives confirmed that the c.995C > T genotype segregates with the ARCA phenotype. Residue Thr332 is conserved across species and among various ethnic groups. The mutation is predicted to be deleterious, most likely due to a protein structure alteration as demonstrated with protein modelling.

Conclusions

This novel disease is the first to demonstrate a neurological role for a transmembrane serine proteases family member. This study demonstrates a proof-of-concept whereby combining exome sequencing with homozygosity mapping can find the genetic cause of a rare disease and acquire better understanding of a poorly described protein in human development.

【 授权许可】

   
2013 Lahiry et al.; licensee BioMed Central Ltd.

【 图 表 】

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