A new story about an old gene

Cécile ACQUAVIVA-BOURDAIN

Service des Maladies Héréditaires du Métabolisme

Hospices Civils de LyonFrance

“Assembly of COX in SURF1-p null mutants is blocked at an early step.

Control

In 1999…, Tiranti et al. reported in LSCOX

BMdeC

and in 2013?....

However, detection of residual amounts of fully assembled complex suggests a certain degree of redundancy.” Hum Mol Genet 1999, 13, 2533-2540

Echaniz et al report SURF1 deficiency in CMTCOX

BMdeC

but markedly reduced, amount of fully assembled complex IV.” Neurology 2013, 81, 1-8

“In the c.107-2A>G samples, the absence of SURF1protein 1 2 3

SURF1

SDHB 1 2 3 4

COX4

MTCO1

SDHA

is associated with a detectable,

BMdeC

nosubassembly species

no

1 2 3 4

COX4

MTCO1

SDHA

18%

8%

c.107-2A>GEchaniz-LagunaNeurology 2013

CMTCOX

3%

6%

p.[Leu105X]+[Ser282CysfsX9]Tiranti Ann Neurol 1999

LSCOX

BMdeC

p.[Leu105X]+[Ser282CysfsX9]

Tiranti 1999c.107-2A>G

1 2 3

SURF1

SDHB

34 kDa

34 kDa

26 kDa

26 kDa

- despite: 1) the abolition of the acceptor splice site of the SURF1 intron 2 : no normally spliced transcripts

Ex1/2 -9 -6 -3/4 Ex 2 -6

- In CMTCOX, such a residual amount of fully assembled complex IV is responsible for residual COX activity: 18% inmuscle (26% in fibroblasts).

2) the absence of SURF1

BMdeC

SURF1 deficiency in CMTCOX

II.10 the 42-year-old probandat age 8: severe demyelinating CMT disease with reduced conduction velocities, axonal loss, hypomyelinated fibers and onion bulb formation

*

x1,000

superficial peronealnerve biopsy

The CMT4 index family

*

x11,925

BMdeC

The CMT4 index family (2)

at age 42: - still able to walk, but no more than 30 m- very slow progression of the CMT disease- nystagmus and mild hearing loss- lactic acidosis (3.3 mmol/l)- no mutation in CMT4-causing genes: PMP22, MPZ, GJB1, GDAP1, PRX, SH3TC2, MTMR2

brain MRIhyperintense lesions in both putamina: typical of LS

MUSCLE and SKIN biopsiesmitochondrial disease suspected

BMdeC

The CMT4 index family (3)

- Morphological examinationCOX deficiency in all muscle fibers

- Spectrophotometric analysisisolated defect of complex IV activity (18%)

- Molecular investigationno variation in: MTCO1, MTCO2, MTCO3, and nuclear TACO1

MUSCLE biopsy

Control Patient

x200)

BMdeC

The CMT4 index family (4)

II.2 the 57-year-old elder sister

before age 10: severe demyelinating polyneuropathy with the same symptoms after age 40: marked cerebellar ataxia, nystagmus, hearing loss, kyphoscoliosis, lactic acidosis

brain MRIunconclusive

MUSCLE biopsywas refused

BMdeC

The CMT4 index family (5)

SURF1 is the disease-causing gene in this CMTCOX family

SURF1 c.107-2A>Gin intron 2

MRI + COX deficiency

Absence of SURF1 but detectable fully assembled complex IV and residual COX activity

1 2

SURF1

SDHB

1 2 3

COX4

MTCO1

SDHA

COX activity: 18%

BMdeC

What about SURF1 in other CMT4 patients?

- in 40 unrelated patients with genetically undefined CMT4- another patient with two additional pathogenic variants: p. [Arg192Trp] + [Leu267GlufsX24]at age 3: severe demyelinating CMT disease at age 10: mild cerebellar ataxia + abnormal MRI

• 3 patients with SURF1-associated CMT4 presented with: severe childhood-onset neuropathy,

motor nerve conduction velocities < 25 m/s, and lactic acidosis.

• 2/3 patients had brain MRI abnormalities, and developed cerebellar ataxia years after polyneuropathy.

• 2/41 families (5%) with disease-causing SURF1 variants

- Is the COX defect modulated as reported in yeaststrains with ablated SHY1 (the SURF1 ortholog)(Bestwick 2010)?+ by adaptative changes with interacting partners (other COX assembly factors, cyt c…) + and/or by adaptative mechanisms (mtCu++ level)

- Is the variable severity of the phenotype associatedwith the absence of SURF1 depending on theefficiency of compensatory genetic or epigeneticmechanisms in humans?

SURF1-associated LSCOX or CMTCOX?

BMdeC

- Similar or identical mutations: why LS or CMT?

BMdeC

SURF1 should be systematically screened in patients with: 1) childhood-onset severe demyelinating neuropathy

2) additional features 3) brain MRI abnormalities4) cerebellar ataxia developing years after polyneuropathy.

Echaniz-Laguna A, Ghezzi D, Chassagne M, Mayençon M, Padet S, Melchionda L, Rouvet I,

Lannes B, Bozon D, Latour P, Zeviani M, Mousson de Camaret B

Strasbourg-Lyon Milan

Neurology 2013, 81, 1523-1530

Supplemental slides

Immunoblotting with monoclonal antibodies

Against MTCOI

Against COX4

SDHA

Immunoblotting with monoclonal antibodies

Against MTCOI

Against COX4

SDHA

Classification des CMT

• Formes démyélinisantes: CMT1

► VCM > 38 m/s (nerf médian)

• Formes axonales: CMT2

► VCM < 38 m/s (nerf médian)

Classification des CMT (suite)

• CMT démyélinisant AD: CMT1

• CMT démyélinisant AR: CMT4

• CMT axonal AD: CMT2

Les CMT dominantes

CMT1A: PMP22CMT1B: MPZCMT1C: LITAFCMT1D: EGR2CMT1X: GJB1

CMT2A: MFN2CMT2B: RAB7CMT2C: TRPV4CMT2D: GARSCMT2E: NEFLCMT2F: HSPB1CMT2P0: MPZ

autosomique dominant

axonal (CMT2)myélinique (CMT1)

Les CMT récessives

CMT4A: GDAP1CMTAB1: MTMR2CMT4B2: MTMR13CMT4C: SH3TC2CMT4D: NDRG1CMT4E: EGR2CMT4F: PRXCMT4H: FGD4CMT4J: FIG4

AR-CMT2A : LMNA

autosomique récessif

myélinique (CMT4) axonal

Ghezzi et Zeviani Adv Exp Med Biol 2012 Assembly factors of respiratory chain complexes