Hereditary spastic paraplegia 17

Summary

Hereditary spastic paraplegia 17 (MONDO:0010043) is a disease caused by BSCL2 (GenCC Strong), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: BSCL2 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 106
• Phenotypes (HPO): 16

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		20	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

16 HPO clinical features (Orphanet curated; top 16 by frequency):

HPO ID	Term	Frequency
HP:0001347	Hyperreflexia	Frequent (30-79%)
HP:0001436	Abnormality of the foot musculature	Frequent (30-79%)
HP:0002064	Spastic gait	Frequent (30-79%)
HP:0003487	Babinski sign	Frequent (30-79%)
HP:0009027	Foot dorsiflexor weakness	Frequent (30-79%)
HP:0009130	Hand muscle atrophy	Frequent (30-79%)
HP:0001171	Split hand	Occasional (5-29%)
HP:0001763	Pes planus	Occasional (5-29%)
HP:0002174	Postural tremor	Occasional (5-29%)
HP:0002936	Distal sensory impairment	Occasional (5-29%)
HP:0003693	Distal amyotrophy	Occasional (5-29%)
HP:0030237	Hand muscle weakness	Occasional (5-29%)
HP:0030838	Hip pain	Occasional (5-29%)
HP:0030839	Knee pain	Occasional (5-29%)
HP:0031374	Ankle weakness	Occasional (5-29%)
HP:0040131	Abnormal motor nerve conduction velocity	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary spastic paraplegia 17
Mondo ID	MONDO:0010043
MeSH	C536644
OMIM	270685
Orphanet	100998
DOID	DOID:0110770
UMLS	C2931276
MedGen	419034
GARD	0004219
Is cancer (heuristic)	no

Also known as: autosomal dominant spastic paraplegia type 17 · BSCL2 hereditary spastic paraplegia · hereditary spastic paraplegia caused by mutation in BSCL2 · hereditary spastic paraplegia type 17 · Silver spastic paraplegia syndrome · Silver syndrome · spastic paraplegia 17 · spastic paraplegia 17, autosomal dominant · spastic paraplegia with amyotrophy of hands and feet · spastic paraplegia-amyotrophy of hands and feet · SPG17

Data availability: 106 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › autosomal dominant complex spastic paraplegia › hereditary spastic paraplegia 17

Related subtypes (12): spastic paraplegia-epilepsy-intellectual disability syndrome, spastic paraplegia-nephritis-deafness syndrome, spastic paraplegia-neuropathy-poikiloderma syndrome, spastic paraplegia-precocious puberty syndrome, hereditary spastic paraplegia 29, hereditary spastic paraplegia 38, hereditary spastic paraplegia 36, spastic paraplegia, intellectual disability, nystagmus, and obesity, autosomal dominant spastic paraplegia type 9, spastic paraplegia-facial-cutaneous lesions syndrome, spastic paraplegia-Paget disease of bone syndrome, spastic paraplegia 18a, autosomal dominant

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

106 retrieved; paginated sample, class counts are floors:

64 uncertain significance, 14 conflicting classifications of pathogenicity, 6 likely benign, 6 pathogenic, 5 likely pathogenic, 4 benign, 4 pathogenic/likely pathogenic, 3 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
372120	NM_001122955.4(BSCL2):c.974dup (p.Ile326fs)	BSCL2	Pathogenic	criteria provided, multiple submitters, no conflicts
4536	NM_001122955.4(BSCL2):c.517dup (p.Thr173fs)	BSCL2	Pathogenic	criteria provided, multiple submitters, no conflicts
4543	NM_001122955.4(BSCL2):c.455A>G (p.Asn152Ser)	BSCL2	Pathogenic	criteria provided, multiple submitters, no conflicts
4544	NM_001122955.4(BSCL2):c.461C>T (p.Ser154Leu)	BSCL2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
476810	NM_001122955.4(BSCL2):c.461C>G (p.Ser154Trp)	BSCL2	Pathogenic	criteria provided, multiple submitters, no conflicts
844412	NM_001122955.4(BSCL2):c.486+1G>A	BSCL2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
947075	NM_001122955.4(BSCL2):c.1361_1386del (p.Arg454fs)	BSCL2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
372119	NM_001122955.4(BSCL2):c.864-2A>G	HNRNPUL2-BSCL2	Pathogenic	criteria provided, single submitter
4539	NM_001122955.4(BSCL2):c.826G>C (p.Ala276Pro)	HNRNPUL2-BSCL2	Pathogenic	criteria provided, multiple submitters, no conflicts
252929	NM_138927.4(SON):c.5753_5756del (p.Val1918fs)	SON	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3383977	NM_001122955.4(BSCL2):c.825dup (p.Ala276fs)	BSCL2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3599919	NM_001122955.4(BSCL2):c.1048C>T (p.Arg350Ter)	BSCL2	Likely pathogenic	criteria provided, single submitter
3599928	NM_001122955.4(BSCL2):c.766-1G>A	BSCL2	Likely pathogenic	criteria provided, single submitter
3599931	NM_001122955.4(BSCL2):c.512_519del (p.Arg171fs)	BSCL2	Likely pathogenic	criteria provided, single submitter
3896785	NM_001122955.4(BSCL2):c.280C>T (p.Gln94Ter)	BSCL2	Likely pathogenic	criteria provided, single submitter
1703084	NM_001122955.4(BSCL2):c.54C>A (p.Cys18Ter)	BSCL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
210545	NM_001122955.4(BSCL2):c.1031C>T (p.Ser344Phe)	BSCL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
246509	NM_001122955.4(BSCL2):c.299G>T (p.Cys100Phe)	BSCL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3599921	NM_001122955.4(BSCL2):c.894C>T (p.Cys298=)	BSCL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3599923	NM_001122955.4(BSCL2):c.864A>G (p.Arg288=)	BSCL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
393431	NM_001122955.4(BSCL2):c.1299TTCTGC[1] (p.434SA[1])	BSCL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
411581	NM_001122955.4(BSCL2):c.1145C>T (p.Ser382Leu)	BSCL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
569480	NM_001122955.4(BSCL2):c.359A>G (p.Tyr120Cys)	BSCL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
617998	NM_001122955.4(BSCL2):c.934G>A (p.Val312Ile)	BSCL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
643607	NM_001122955.4(BSCL2):c.460T>G (p.Ser154Ala)	BSCL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
700938	NM_001122955.4(BSCL2):c.532C>G (p.Leu178Val)	BSCL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
952140	NM_001122955.4(BSCL2):c.1004A>C (p.Gln335Pro)	BSCL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
955662	NM_001122955.4(BSCL2):c.466A>G (p.Thr156Ala)	BSCL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
128532	NM_001122955.4(BSCL2):c.1280T>C (p.Leu427Pro)	HNRNPUL2-BSCL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1024491	NM_001122955.4(BSCL2):c.1022G>A (p.Arg341Lys)	BSCL2	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 16 · Orphanet: 5 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
BSCL2	Strong	Autosomal dominant	hereditary spastic paraplegia 17	16

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
BSCL2	Orphanet:100998	Autosomal dominant spastic paraplegia type 17
BSCL2	Orphanet:139536	Distal hereditary motor neuropathy type 5
BSCL2	Orphanet:363400	Progressive encephalopathy-severe neurodegeneration-lipodystrophy syndrome
BSCL2	Orphanet:696289	Congenital generalized lipodystrophy type 2
SON	Orphanet:500150	ZTTK syndrome

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
BSCL2	HGNC:15832	ENSG00000168000	Q96G97	Seipin	gencc,clinvar
SON	HGNC:11183	ENSG00000159140	P18583	Protein SON	clinvar
HNRNPUL2-BSCL2	HGNC:49189	ENSG00000234857		HNRNPUL2-BSCL2 readthrough (NMD candidate)	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
BSCL2	Seipin	Plays a crucial role in the formation of lipid droplets (LDs) which are storage organelles at the center of lipid and energy homeostasis.
SON	Protein SON	RNA-binding protein that acts as a mRNA splicing cofactor by promoting efficient splicing of transcripts that possess weak splice sites.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 2 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Scaffold/PPI	1	5.8×	0.327
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BSCL2	Other/Unknown	no		Seipin
SON	Scaffold/PPI	no		G_patch_dom, dsRBD_dom,
HNRNPUL2-BSCL2	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
pituitary gland	1
primary visual cortex	1
superior frontal gyrus	1
cardia of stomach	1
pylorus	1
tendon of biceps brachii	1
islet of Langerhans	1
stromal cell of endometrium	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BSCL2	149	ubiquitous	marker	superior frontal gyrus, primary visual cortex, pituitary gland
SON	304	ubiquitous	marker	pylorus, tendon of biceps brachii, cardia of stomach
HNRNPUL2-BSCL2	134		yes	stromal cell of endometrium, ventricular zone, islet of Langerhans

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SON	2,683
BSCL2	1,503
HNRNPUL2-BSCL2	0

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SON	P18583	4
BSCL2	Q96G97	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 3 evidence-associated genes (0 with Reactome annotation).

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
lipid droplet formation	1	495.6×	0.009	BSCL2
lipid droplet organization	1	468.1×	0.009	BSCL2
regulation of mRNA splicing, via spliceosome	1	443.5×	0.009	SON
negative regulation of lipid catabolic process	1	421.3×	0.009	BSCL2
lipid storage	1	271.8×	0.011	BSCL2
mitotic cytokinesis	1	129.6×	0.017	SON
lipid catabolic process	1	122.1×	0.017	BSCL2
regulation of RNA splicing	1	109.4×	0.017	SON
fat cell differentiation	1	90.6×	0.018	BSCL2
positive regulation of cold-induced thermogenesis	1	81.8×	0.018	BSCL2
microtubule cytoskeleton organization	1	60.6×	0.022	SON
RNA splicing	1	44.1×	0.028	SON
mRNA processing	1	39.4×	0.029	SON
regulation of cell cycle	1	37.3×	0.029	SON
negative regulation of apoptotic process	1	17.4×	0.057	SON

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SON	1	2
BSCL2	0	0
HNRNPUL2-BSCL2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	SON

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
SON	7	Binding:7

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

1 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
MOLIBRESIB	2	SON

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	SON
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	BSCL2, HNRNPUL2-BSCL2

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
BSCL2	0	—
HNRNPUL2-BSCL2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.