A novel variant (p.A524P) in Spastin is responsible for a Chinese family with hereditary spastic paraplegia.

BACKGROUND: Hereditary spastic paraplegia (HSP) represents a group of monogenic neurodegenerative disorders characterized by high clinical and genetic heterogeneity. HSP is characterized by slowly progressing hypertonia of both lower extremities, spastic gait, and myasthenia. The most prevalent autosomal dominant form of HSP, known as spastic paraplegia 4 (SPG4), is attributed to variants in the spastin (SPAST) gene. METHODS AND RESULTS: Here, a Chinese family presenting with spasticity in both legs and a shuffling gait participated in our investigation. Whole exome sequencing of the proband was utilized to identify the genetic lesion in the family. Through data filtering, Sanger sequencing validation, and co-separation analysis, a novel variant (NM_014946.3: c.1669G > C:p.A557P) of SPAST was identified as the genetic lesion of this family. Furthermore, bioinformatic analysis revealed that this variant was deleterious and located in a highly evolutionarily conserved site. CONCLUSION: Our study confirmed the diagnosis of SPG4 in this family, contributing to genetic counseling for families affected by SPG4. Additionally, our study broadened the spectrum of SPAST variants and highlighted the importance of ATPases associated with various cellular activity domains of SPAST.

A de novo Mutation (p.Gln277X) of Cyclin D2 is Responsible for a Child with Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus Syndrome.

Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH), a type of overgrowth syndrome, is characterized by progressive megalencephaly, cortical brain malformations, and distal limb anomalies. Previous studies have revealed that the overactivity of the phosphatidylinositol 3-kinase-Protein kinase B pathway and the increased cyclin D2 (CCND2) expression were the main factors contributing to this disease. Here, we present the case of a patient who exhibited megalencephaly, polymicrogyria, abnormal neuronal migration, and developmental delay. Serum tandem mass spectrometry and chromosome examination did not detect any metabolic abnormalities or copy number variants. However, whole-exome sequencing and Sanger sequencing revealed a de novo nonsense mutation (NM_001759.3: c.829C>T; p.Gln277X) in the CCND2 gene of the patient. Bioinformatics analysis predicted that this mutation may disrupt the structure and surface charge of the CCND2 protein. This disruption could potentially prevent polyubiquitination of CCND2, leading to its resistance against degradation. Consequently, this could drive cell division and growth by altering the activity of key cell cycle regulatory nodes, ultimately contributing to the development of MPPH. This study not only presents a new case of MPPH and expands the mutation spectrum of CCND2 but also enhances our understanding of the mechanisms connecting CCND2 with overgrowth syndromes.